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Objectives To describe current resistance to the β-lactams empirically recommended in the guidelines in bloodstream infection (BSI) episodes caused by Gram-negative bacilli (GNB). Methods Retrospective, multicentre cohort study of the last 50 BSI episodes in haematological patients across 14 university hospitals in Spain. Rates of inappropriate empirical antibiotic therapy (IEAT) and impact on mortality were evaluated. Results Of the 700 BSI episodes, 308 (44%) were caused by GNB, mainly Escherichia coli (141; 20.1%), Klebsiella spp. (56; 8%) and Pseudomonas aeruginosa (48; 6.9%). Among GNB BSI episodes, 80 (26%) were caused by MDR isolates. In those caused by Enterobacterales, 25.8% were ESBL producers and 3.5% were carbapenemase producers. Among P. aeruginosa BSI episodes, 18.8% were caused by MDR isolates. Overall, 34.7% of the isolated GNB were resistant to at least one of the three β-lactams recommended in febrile neutropenia guidelines (cefepime, piperacillin/tazobactam and meropenem). Despite extensive compliance with guideline recommendations (91.6%), 16.6% of BSI episodes caused by GNB received IEAT, which was more frequent among MDR GNB isolates (46.3% versus 6.1%; P Conclusions Current resistance to empirical β-lactams recommended in febrile neutropenia guidelines is exceedingly high and IEAT rates are greater than desired. There is an urgent need to adapt guidelines to current epidemiology and better identify patients with a high risk of developing MDR GNB infection.

BACKGROUND The karyotype is a predictor of outcomes in adults with acute lymphoblastic leukemia (ALL). The unfavorable prognostic significance of complex karyotype (CK) has been reported, whereas the prognostic relevance of monosomal karyotype (MK) has not been consistently evaluated. We aimed to assess the prognostic value of CK and MK in adults with ALL treated with risk-adapted protocols of the Spanish PETHEMA Group. METHODS The karyotypes of 881 adult ALL patients treated according to the protocols of the PETHEMA Group between 1993 and 2012 were centrally reviewed. CK and MK were assessed according to Moorman's criteria, and Breem's criteria, respectively. Specific analyses according to the risk groups and to the presence of t(9:22) were performed. RESULTS Of 364 evaluable patients 33 (9.2%) had CK, and 68 of 535 evaluable patients (12.8%) had MK. Complete remission rate, remission duration, and overall survival were not significantly different according to the presence of CK or MK in the whole series, according to the B or T lineage, in the high-risk group, or in patients with t(9;22), regardless of imatinib treatment, and in patients who received chemotherapy alone or chemotherapy followed by stem cell transplantation CONCLUSIONS Our study shows that CK and MK were not associated with a worse prognosis in adult patients with ALL treated with risk-adapted or subtype-oriented protocols. In patients with Ph+ ALL, MK did not have an impact on prognosis irrespective of imatinib treatment. Cancer. © 0000 American Cancer Society Cancer 2014;120:3958–3964. © 2014 American Cancer Society.

For PETHEMA Programa para el Estudio de la Terapéutica en Hemopatías Malignas Cooperative Study Group., The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (≥0.1%; ≥0.01-0.1%; and, This work was supported in part by Spanish grants from Fondo de Investigación Sanitaria-ISCIII (FIS 00/0023-03, PI12/02321), DGCYT (SAF 94- 0308, SAF2001-1687), Conserjería de Educación de Castilla y León (HUS416A12), and Red Temática de Investigación Cooperativa en Cáncer (RTICC-ISCIII) (RD12/0036/0069).

Background and objective Several studies have demonstrated the feasibility of autologous stem cell transplantation (ASCT) in patients with lymphoma and human immunodeficiency virus (HIV) infection. HIV infection has been described as a risk factor for poor mobilization. The aim of this study was to compare the results of two mobilization strategies of peripheral blood stem cells (PBSC) in patients with lymphoma and HIV infection in seven Spanish hospitals.

The PI3/AKT pathway is up-regulated in acute myeloid leukemia (AML), but its prognostic relevance in cytogenetically normal AML (CN-AML) is unclear. We evaluated RNA levels of AKT and two downstream substrates (FOXO3a-p27) in 110 de novo CN-AML, included in the Spanish PETHEMA therapeutic protocols. Patients with high FOXO3a gene expression displayed shorter OS (p = 0.015) and RFS (p = 0.048) than low FOXO3a expressers. Features selected in the multivariate analysis as having an independent prognostic value for a shorter survival were WBC > 50 × 109/L, age >65 years and high FOXO3a expression. We concluded that FOXO3a assessment could contribute to improve the molecular-based risk stratification in CN-AML. © 2009 Elsevier Ltd. All rights reserved., This work has been partially supported with the grants PI061351 and 00/0023-00 from the Spanish “Fondo de Investigaciones Sanitarias de la Seguridad Social”, 89/A/06 from “Gerencia Regional de Salud, Junta Castilla y León”, CR-USA Foundation-Spanish National Research Council (CSIC) Cooperative Agreement and CIC, IBMCC (USAL-CSIC), Spain.

The karyotype is a predictor of outcomes in adults with acute lymphoblastic leukemia (ALL). The unfavorable prognostic significance of complex karyotype (CK) has been reported, whereas the prognostic relevance of monosomal karyotype (MK) has not been consistently evaluated. We aimed to assess the prognostic value of CK and MK in adults with ALL treated with risk-adapted protocols of the Spanish PETHEMA Group.The karyotypes of 881 adult ALL patients treated according to the protocols of the PETHEMA Group between 1993 and 2012 were centrally reviewed. CK and MK were assessed according to Moorman's criteria, and Breem's criteria, respectively. Specific analyses according to the risk groups and to the presence of t(9:22) were performed.Of 364 evaluable patients 33 (9.2%) had CK, and 68 of 535 evaluable patients (12.8%) had MK. Complete remission rate, remission duration, and overall survival were not significantly different according to the presence of CK or MK in the whole series, according to the B or T lineage, in the high-risk group, or in patients with t(9;22), regardless of imatinib treatment, and in patients who received chemotherapy alone or chemotherapy followed by stem cell transplantationOur study shows that CK and MK were not associated with a worse prognosis in adult patients with ALL treated with risk-adapted or subtype-oriented protocols. In patients with Ph+ ALL, MK did not have an impact on prognosis irrespective of imatinib treatment.

Purpose Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation. Patients and Methods Patients with good early cytologic response (< 10% blasts in bone marrow at day 14 of induction) and a flow-MRD level less than 5 × 10−4 at the end of consolidation were assigned to delayed consolidation and maintenance therapy, and allo-HSCT was scheduled in patients with poor early cytologic response or flow-MRD level ≥ 5 × 10−4. Results Complete remission was attained in 282 (87%) of 326 patients, and 179 (76%) of 236 patients who completed early consolidation were assigned by intention-to treat to receive allo-HSCT (71) or chemotherapy (108). Five-year disease-free survival (DFS) and overall survival (OS) probabilities were 37% and 35% for the whole series, 32% and 37% for patients assigned to allo-HSCT, and 55% and 59% for those assigned to chemotherapy. Multivariable analysis showed poor MRD clearance (≥ 1 × 10−3 after induction and ≥ 5 × 10−4 after early consolidation) as the only prognostic factor for DFS and OS. Conclusion Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS.

Several studies have demonstrated the feasibility of autologous stem cell transplantation (ASCT) in patients with lymphoma and human immunodeficiency virus (HIV) infection. HIV infection has been described as a risk factor for poor mobilization. The aim of this study was to compare the results of two mobilization strategies of peripheral blood stem cells (PBSC) in patients with lymphoma and HIV infection in seven Spanish hospitals.The following variables were collected: demographic, clinical and biological features, previous chemotherapies and outcomes, as well as mobilization's strategies (classified in two groups: 1) G-CSF, and 2) G-CSF + chemotherapy).Between January 2000 and May 2010, 42 patients with lymphoma and HIV infection were referred for ASCT. The rate of successful mobilization (collection1.60 × 10(6) CD34 cells/kg) with the first regimen was 67%, with no differences between those patients mobilized with G-CSF or with G-CSF + chemotherapy (16 [72%] and 12 [60%], respectively; p=0.382). The status of the lymphoma at the time of mobilization was the only factor for successful mobilization (20/22 patients [91%] in complete remission [CR] mobilized adequately versus 5/12 [58%] in partial remission [PR]; p=0.038).In patients with lymphoma and HIV infection, mobilization with G-CSF was as effective as mobilization with chemotherapy followed by G-CSF. The stage of disease prior to the mobilization was the main risk factor for the success of mobilization, with better results in patients mobilized in remission of the lymphoma.

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.

Fundamento y objetivo: La infiltracion del sistema nervioso central (SNC) en pacientes diagnosticados de leucemia aguda (LA) es una complicacion infrecuente que comporta un mal pronostico. La indicacion y las pautas de profilaxis y tratamiento de la infiltracion neuromeningea en la LA no son homogeneas en los diferentes paises, y tampoco en los diferentes centros de un mismo pais. El objetivo de este estudio longitudinal y prospectivo ha sido describir la practica real de profilaxis y tratamiento de la infiltracion neuromeningea en pacientes con LA en Espana. Pacientes y metodo: Se trata de un estudio prospectivo llevado a cabo desde junio de 2005 a junio de 2006. Se incluyo, mediante registro electronico, a los pacientes adultos (edad $ 18 anos) diagnosticados de LA que recibieron profilaxis o tratamiento de la infiltracion del SNC. Resultados: Se incluyo a un total de 265 pacientes procedentes de 32 hospitales. La media (desviacion estandar) de edad fue de 44 (16) anos y 133 (50%) eran varones. Entre los 158 pacientes con leucemia linfoblastica aguda, 12 (10 en el momento del diagnostico y 2 en recaida) recibieron tratamiento del SNC por infiltracion neuromeningea, que consistio en tratamiento intratecal triple (TIT: metotrexato, citarabina e hidrocortisona) en 11 casos y citarabina liposomica de liberacion lenta por via intratecal en uno. La profilaxis del SNC administrada en los 146 pacientes restantes incluyo TIT en 135 casos, metotrexato intratecal en 7, citarabina intratecal en 2 y citarabina liposomica de liberacion lenta por via intratecal en 2. No se administro radioterapia craneal ni craneoespinal a ningun paciente. Entre los 107 pacientes con leucemia mieloblastica aguda, 17 tenian infiltracion del SNC (9 en el momento del diagnostico y 8 en la recaida). El tratamiento intratecal consistio en TIT en 11 casos, citarabina liposomica de liberacion lenta en 5 y citarabina intratecal en uno. Un paciente recibio ademas radioterapia craneoespinal. La profilaxis del SNC en los 90 pacientes restantes incluyo TIT en 68 casos y metotrexato intratecal en 22. Conclusiones: En Espana las pautas de profilaxis y tratamiento de la infiltracion neuromeningea en pacientes con LA son homogeneas. El TIT fue el esquema usado con mayor frecuencia tanto para la profilaxis como para el tratamiento del SNC. Llama la atencion la escasa utilizacion de la radioterapia holocraneal o craneoespinal, asi como la administracion de nuevos farmacos, como la citarabina liposomica de liberacion lenta, en el tratamiento y la profilaxis de la meningosis leucemica.

Purpose Retrospective studies have shown that adolescents and young adults with acute lymphoblastic leukemia (ALL) treated with pediatric protocols have better outcomes than similarly aged patients treated with adult protocols, but prospective studies comparing adolescents and young adults using pediatric schedules are scarce. The ALL-96 protocol was addressed to compare the toxicity and results of a pediatric-based protocol in adolescents (age 15-18 years) and young adults (age 19-30 years) with standard-risk (SR) ALL. Patients and Methods Adolescents (n = 35) and young adults (n = 46) received a standard five-drug/5-week induction course followed by two cycles of early consolidation, maintenance with monthly reinforcement cycles up to 1 year in continuous complete remission (CR) and 1 year with standard maintenance chemotherapy up to 2 years in CR. Results Adolescents and young adults were comparable in the main pretreatment ALL characteristics. The CR rate was 98% and. after a median follow-up of 4.2 years, 6-year event-free survival (EFS) and overall survival (OS) were 61% (95% CI, 51% to 72%) and 69% (95% CI, 59% to 79%), respectively, with no differences between adolescents and young adults. The hematologic toxicity in consolidation and reinforcement cycles was higher in young adults than in adolescents. Slow response to induction therapy was the only parameter associated with poor EFS (34% v 67%) and OS (40% v 76%). Conclusion The response to the pediatric ALL-96 protocol was identical in adolescents and young adults despite a slight increase in hematologic toxicity observed in adults. This justifies the age-unrestricted use of pediatric regimens to treat patients with SR ALL.

Intrathecal (IT) depot liposomal cytarabine is useful in solid tumors or lymphomatous meningitis, but has scarcely been used in central nervous system (CNS) involvement in acute leukemia. We report the results of compassionate therapy with IT depot liposomal cytarabine in 10 patients with acute myeloid leukemia with CNS involvement. Five of 6 cases receiving this drug as the only IT therapy and the remaining 4 receiving it as adjuvant therapy to other CNS-directed therapies showed clearance of cerebrospinal fluid blast cells, with sustained response in 5 and mild side effects. Systemic therapy was given concomitantly in all cases, with high-dose cytarabine in 6. Clinical trials should establish the role of IT liposomal cytarabine in leukemic meningitis.

INTRODUCTION AND AIMS Almost seventy percent of Acute Myeloid Leukemia (AML) patients will relapse. Fludarabine, Ara-C, Idarrubicine, G-CSF (FLAG-Ida) and FLAG-Ida and Gentuzumab-Ozogamicin (FLAGO-Ida) is frequently used before allogenic stem cell transplant (ASCT). There are several studies analyzing the risk factors for survival in relapsed/refractory patients, but none of them were performed exclusively in patients treated with FLAG-Ida. We analyzed the results of in the Spanish trials conducted by PETHEMA. We also present a predictive score system of survival prognosis based on the data of the patients enrolled METHODS This is a retrospective, multicentre study of the PETHEMA AML epidemiologic Registry. In PETHEMA protocols 98,99,2007,2010 and 2011, FLAG-Ida was included as salvage treatment in patients relapsed or resistant after a 2ndinduction based in 3+7. In PETHEMA trial 2007, FLAG-Ida (or FLAGO-Ida) was administered if complete remission (CR) was not attained in the first induction cycle. The use of FLGO in PETHEMA 2007 trial depended on the availability of GO for each centre. We use overall survival (OS) as final end point of the analysis. Univariate survival analysis was performed by Long-Rank test. Stepwise backward variable selection and Cox proportional hazard multivariable analysis was performed (covariables selected if p RESULTS We analyzed 259 patients consecutively registered between 1999 and 2012. The median age was 52 (16-76) and the median follow-up of the patients still alive was 23 months. Only 38 (14%) patients received FLAGO-Ida as salvage treatment. Favorable karyotype (inv 16) and t(8;21) was present in 13 (6%) and 11 (5%) respectively; intermediate in 145 (62%) and adverse in 62 (21%). Previous ASCT was performed in 86 patients (33%). The number of patients who achieved CR or CR without recovery of peripheral counts (CRi) was 132 (52%), PR in 23 (9%). Resistance accounted for 75 (29%) and death for 24 (9%). For the purposes of the current study, we decided to include patients with t(8;21) in the group of adverse karyotype group due to the similar median OS compared with MRC adverse karyotype (Median OS,0,42 vs 0,45 years). In univariate analysis karytotype (p=0.0001), FLT3-ITD positive (p=0.005), previous transplant (comparing no transplant, autologous and allogenic, p=0.012) and time to relapse (comparing refractory vs 12 months; p=0.0002) were significant risk factors. Contrary to other studies previous ASCT was associated to better outcome (median OS=2.3years, p=0.012). In multivariate analyses, the following variables remained as independent risk factors for survival: TTT (p=0.003), cytogenetic risk (p12 months: 0, refractory: 2, relapsed8 points, 44.6% of patients, median OS 0.4 years). CONCLUSIONS: This retrospective study based on an Epidemiologic Registry, shows that in primary refractory and first relapsed AML patients, the use FLAG-Ida or FLAGO-Ida salvage regimens lead to 52% of second CR. In addition, we have developed a scoring system using FLT3-ITD, refined cytogenetics, previous ASCT and TTT that can predict survival, identifying before administering FLAG-IDA a good prognosis population representing 27% of patients in which FLAG-IDA (followed by ASCT) can be an optimal therapy. This prognostic index should be validated in an independent cohort. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Patients with primary refractory Hodgkin’s disease (PR-HD) have a dismal prognosis when treated with conventional salvage chemotherapy. We analyzed time to treatment failure (TTF), overall survival (OS) and clinical variables influencing the outcome in patients undergoing autologous stem cell transplantation (ASCT) for PR-HD and reported to the Grupo Espanol de Linfomas/Trasplante Autologo de Medula Osea (GEL/TAMO). Patients and methods: Sixty-two patients, 41 males and 21 females with a median age of 27 years (range 13–55) were analyzed. Forty-two patients (68%) had advanced stage at diagnosis, 47 (76%) presented with B symptoms and 29 (47%) with a bulky mediastinal mass. Seventy-five percent of the patients had received more than one line of therapy before ASCT. Thirty-three patients received bone marrow as a source of hematopoietic progenitors, and 29 peripheral blood. Six patients were conditioned with high-dose chemotherapy plus total-body irradiation and 56 received chemotherapy-based protocols. Results: One-year transplantation-related mortality was 14% [95% confidence interval (CI) 6% to 23%]. Response rate at 3 months after ASCT was 52% [complete remission in 21 patients (34%), partial remission in 11 patients (18%)]. Actuarial 5-year TTF and OS were 15% (95% CI 5% to 24%) and 26% (95% CI 13% to 39%), respectively. The presence of B symptoms at ASCT was the only adverse prognostic factor significantly influencing TTF [relative risk (RR) 1.75, 95% CI 0.92–3.35, P = 0.08]. The presence of B symptoms at diagnosis (RR 2.08, 95% CI 0.90–4.79, P = 0.08), MOPP-like regimens as first-line therapy (RR 3.84, 95% CI 1.69–9.09, P = 0.001), bulky disease at ASCT (RR 2.79, 95% CI 0.29–6.03, P = 0.009) and two or more lines of therapy before ASCT (RR 2.24, 95% CI 0.95–5.27, P = 0.06) adversely influenced OS. Conclusions: In our experience, although overall results of ASCT in PR-HD patients are poor, one-quarter of the patients remain alive at 5 years. Despite this, other therapeutic strategies should be investigated in this group of patients to improve the outcome.

Short, intensive multiagent chemotherapy has resulted in significant progress in Burkitt's lymphoma and leukemia. A protocol was designed to treat all adult patients with mature B-cell lymphoma or leukemia with the aims of comparing the response to therapy and survival with regards to their HIV infection status.Fifty-three adult patients with advanced stage Burkitt's lymphoma or Burkitt's leukemia were treated. Response to therapy, survival and toxicity were evaluated according to their HIV infection status.The median age of the patients was 53 years (range 15-74). There were no differences in CR rates between HIV-negative (77%) and HIV-positive patients (71%). Only age60 years was associated with a lower CR rate (OR 0.18, 95%CI 0.04-0.81, p=0.026). The 2-year overall survival (OS) probability was 51% (95%CI, 38%-64%) for the 53 patients. The OS of HIV-negative and HIV-positive patients did not significantly differ. Only age60 years was associated with a shorter OS (OR 5.1, 95%CI 2.0-12.7, p=0.001). The 2-year disease free survival (DFS) for the 40 patients achieving CR was 60% (95%CI, 45%-75%). Age60 years was the only identified factor associated with a shorter DFS (OR 5.2, 95%CI 1.4-20, p=0.015).This study confirms the effectiveness of intensive strategies in adult patients with advanced stage Burkitt's lymphoma or leukemia. It also shows the feasibility of these strategies in individuals with HIV infection with comparable results. Advanced age proved to be the main adverse prognostic factor for response to therapy and survival.

Abstract 4785 Background The karyotype is an important predictor of outcome in adults with acute lymphoblastic leukemia (ALL). Some groups have reported the negative prognostic value of complex karyotype (CK, defined as ≥5 unrelated chromosomal abnormalities) in adult ALL (Moorman et al, Blood. 2007:109;3189-97). On the other hand, monosomal karyotype (MK, defined as ≥2 distinct autosomal chromosome monosomies or 1 single monosomy in the presence of structural abnormalities) has been associated with a worse outcome in patients with acute myeloid leukemia. We aimed to assess the prognostic value of cytogenetic abnormalities, especially CK and MK, in adults with ALL treated with protocols of the Spanish PETHEMA Group. Patients and Methods The karyotypes of 783 adult ALL patients from 63 Spanish centers treated according to the protocols of the PETHEMA Group between 1993 and 2011 were reviewed. The several PETHEMA protocols were risk-adapted (standard-risk –SR–, high-risk –HR–) or subtype-oriented (Philadelphia chromosome [Ph+] ALL -with or without imatinib-, and Burkitt's ALL [BL]). The impact of the main cytogenetic abnormalities as well as of the CK and MK on complete remission (CR) rate, CR duration, overall survival (OS) and event-free survival (EFS) was analyzed. Results The median age of the series was 33 years (range 15–82) and 448 patients (57.2%) were male. The karyotypes of 560 out of 783 patients were evaluable after review: normal karyotype 153 patients, t(9;22) 120, t(v;11q23) 30, t(8;14), t(8;22) or t(2;8) 47, high hyperdiploidy (>50 chromosomes) 53, low hyperdiploidy (47–50 chromosomes) 52, hypodiploidy (45–39 chromosomes) 32 and extreme hypodiploidy ( Conclusions Our study confirms that cytogenetics is a very important tool for risk assessment in adult ALL. Patients with t(9;22) and t(v;11q23) had the worst prognosis and the t(1;19) did not have prognostic significance. The introduction of imatinib in patients with t(9:22) ALL significantly improved their outcome. The CK and the MK were not associated with a worse prognosis in patients treated with risk-adapted or subtype-oriented protocols of the PETHEMA group. Disclosures: No relevant conflicts of interest to declare.

Abstract 2582 Background and objectives. Concurrent imatinib and chemotherapy followed by allogeneic stem cell transplantation (SCT) is the most used treatment for young patients with Ph+ALL. However, the amount of chemotherapy before SCT is not well established. The Spanish PETHEMA Group conducted two consecutive protocols (CSTIBES02 -Haematologica 2010; 95: 87–95- and ALL Ph08) differing in the imatinib dose (400 mg/d vs. 600 mg/d) and the amount of chemotherapy (two consolidation cycles vs. one consolidation cycle) before SCT. The short –term outcomes are herein compared. Patients and methods. CSTIBES02 trial included 30 patients with a median age of 44 yr and ALL Ph08 includes 26 patients (median age 37 yr). The main clinical and biological features of the two series of patients are comparable. The initial induction chemotherapy schedule included VCR, DNR and PDN at the same doses in the two protocols, but in the CSTIBES02 mitoxantrone and ARA-C were administered on day 15 if >5% blast cells were present in bone marrow smear, whereas no change in the chemotherapy schedule was prescribed in the ALL Ph08 trial according to the percentage of blast cells on day 15. The first consolidation cycle included HD MTX, ID ARA-C, MP and teniposide in both protocols. Patients in CR were then submitted to SCT in ALL Ph08 study, whereas those included in CSTIBES02 received a second consolidation cycle before SCT. Imatinib was administered concurrently with chemotherapy from diagnosis (400 mg/d in CSTIBES02 trial and 600 mg/d in ALL Ph08 study). Results. The main short-term outcomes are compared in the table Conclusion. Despite non-significant improvement has been observed in ALL Ph08 protocol regarding CR attainment, molecular response after induction and consolidation, 2-yr EFS has been improved after the increase of imatinib dose and the decrease of amount of chemotherapy. Both decrease in relapse before SCT and TRM observed in the ALL Ph08 protocol are responsible for the better EFS. Supported in part by grants RD06/0020/1056 from RTICC and P-EF-11 from FJC Disclosures: No relevant conflicts of interest to declare.

Abstract 4279 Introduction: Clofarabine (CLF) is a purine nucleoside analog approved by FDA and EMA in refractory pediatric ALL patients. Phase I and II studies have reported Clofarabine activity in AML. Aims: To evaluate the experience in Spain with (CLF) in the treatment of adult AML patients, analyzing effectiveness and toxicity profile. Method: This is a multicenter retrospective study including AML patients treated in Spain with CLF by compassionate use. Main points were complete remission as IWRv2003 criteria and toxicity as CTCAE v3.0 of NCI scale. Result: Between July 2007 ans April 2011 a total of 76 AML patients were treated with CLF based chemotherapy in Spain. We obtained clinical data from 64 cases. Median age at CLF treatment 52.4 years (18–77). Male/Female: 31/33. Previous Myelodisplastic syndrome 12 (18%). Cytogenetic data was available in 58 patients (90%), and 28 of them had high-risk cytogenetic. CLF treatment: 56 patients received CLF as salvage therapy (23 in AML relapse and 33 in refractory disease), median previous lines 2 (0–7), were the remaining 8 patients were untreated patients. CLF was administered in combination with AraC in 94% patients and the 91% received a five days schedule. The most frequents CLF dose/day were: 40 mg/m2/day in 39 patients, 30 mg/m2/day in 11 patients, and 20 mg/m2/day in 9 patients. Response and outcome: Nineteen (35.8%) patients achieved complete remission and 64.1% had resistant disease. Mean survival time 14.3 ± 1.4 months. The statistical analysis shows a significant difference in the CR rate between first line therapy (CR 82%) and savage therapy in relapsed (CR 45%) and salvage therapy in refractory (CR 18%), (p0.012). Neither adverse cytogenetics nor previous MDS did influence CR. (p0.57 and p0.53 respectively). Toxicity: All patients presented grade IV hematological toxicity with grade IV neuthopenia, grade IV trombopenia and transfusion depend anemia. The incidence of extra hematological toxic effects were low, creatinine >3 mg/dL: 4 cases (6%); bilirrubine > 3mg/dL: 9 cases (14%). Eleven (17%) patients died during Induction. Conclusions(opcion1): The revised experience in Spain with CLF as compassionate used in AML confirms the effectiveness of Clofarabine as a salvage regimen. Of note was that CLF could potentially overcome some adverse known factors as cytogenetics. Disclosures: Off Label Use: Clofarabine in AML is an off-label use.

Abstract 322 Introduction: Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance ( Patients and methods: HR ALL included one or more of the following baseline parameters: age 30–60 yr, WBC count >25×109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level Results: On June 2009, 235 HR ALL pts were evaluable [mean (SD) age 37(14) yr, 129 males, 155 precursor B-ALL, 80 T-ALL, WBC count 64(96) ×109/L]. Induction death: 20(8%), resistance: 11 (5%), CR: 202 (87%). Slow cytologic response on d14 was observed in 137/186 (74%) pts, MRD Conclusions: These results suggest that in HR Ph- adult ALL pts with adequate response to induction and adequate clearance of MDR after consolidation the results of therapy are not hampered by avoiding allogeneic SCT. MRD is the main prognostic factor for CR, DFS and OS. Supported by grants P-EF/07 from FIJC and RD 06/0020/10556 from RETICS, and PI051490 from FIS, Instituto Carlos III. Disclosures: No relevant conflicts of interest to declare.

Several mutations and aberrant gene expression have been proposed as prognostic factors in cytogenetically normal acute myeloid leukemia (CN-AML), but few studies have analyzed the clinical value of several genes in a large group of CN-AML patients. In 121 de novo CN-AML included into the Spanish PETHEMA therapeutic protocols, we evaluated FLT3 and NPM1 mutations and BAALC , ERG , EVI1 , MLL -PTD, MN1 , PRAME , RHAMM and WT1 RNA levels. Ninety-one patients achieved CR with standard induction therapy while 20/111 (16.5%) were refractory to treatment. This latter subgroup showed higher ERG (media 1.0±0.8 vs. 0.6±0.6;p=0.012) and lower PRAME (media 28.8±52.9 vs. 1640.6±6102.0;p=0.014) levels than no-refractory patients. Moreover, high ERG expression (defined by median value) was associated with shorter OS at 2-years (38% vs. 61%;p=0.012) and RFS at 2-years (38% vs. 60%;p=0.005). By contrast, high PRAME levels (defined by 75 th percentile) was related to longer OS (61% vs. 48%;p=0.029) and RFS (74% vs. 43%;p=0.016). Additionally, high EVI expression (defined by 75 th percentile) was associated with a poorer OS (37% vs. 56%;p=0.049). The same results in OS were observed in patients with high BAALC RNA levels (median value; 41% vs. 62%; p=0.049). Interestingly, ERG , EVI1 and PRAME markers improved the current prognostic classification of CN-AML based on FLT3 and NPM1 status. Therefore, intermediate risk patients ( FLT3-ITD/NPM1mut and FLT3wt/NMP1wt ) with low ERG , low EVI1 or high PRAME achieved long OS and RFS, similar to the favorable FLT3 wt/ NPM1 mut subgroup. By contrast, the opposite expression subgroup (high ERG , high EVI1 or low PRAME ) showed OS and RFS similar to the adverse FLT3 -ITD/ NPM1 wt subset. These results allowed identify clearly two risk-subgroups for OS and RFS, based on three molecular markers ( FLT3 , NPM and one of the 3 proposed genes). In conclusion, we demonstrated that ERG , EVI1 and PRAME are relevant prognostics markers in CN-AML and they could improve their risk-stratification.

Elderly patients with acute myeloid leukemia (AML) have an unfavorable outcome, which has been related to both the poor performance status of many of these patients and the biological characteristics of the malignant clone, including the expression of multidrug resistance (MDR) phenotypes. We have quantitatively analyzed by flow cytometry the expression of apoptosis- (bcl-2, bax, APO2.7) and MDR- (P-gp, MRP, LRP) associated proteins in a group of 117 elderly (>65 years) uniformly treated de novo AML patients according to the Pethema LMA-98 protocol. Upon analyzing factors influencing the response to induction therapy, as expected, patients with good and intermediate cytogenetics (n=76) more frequently achieved morphological complete remission (mCR) (63%) than patients having poor cytogenetics (n=23) (mCR: 30%). In addition, CD34 expression also influenced response; thus, 81% (21/26) of CD34-negative patients achieved mCR vs only 46% (42/91) of CD34-positive cases (p=0,008). Neither age nor WBC counts showed a significant influence in response rate. As far as apoptosis and MRD proteins is concerned, interestingly, responding cases showed a lower expression of the bcl-2, MRP and LRP proteins (bcl-2 RFI (relative fluorescence intensity) 10±5.5 vs 13±6, p=0.02; MRP RFI 1.9±0.8 vs 2.7±1.8, p=0.008; LRP RFI 6.2±4.9 vs 8.7±7.5, p=0.01 in responding vs non-responding patients). By contrast, expression of APO 2.7, Bax, and MDR-1 did not influenced response. Analysis of relapse free survival showed that only the number of cycles of chemotherapy required to achieve mCR had prognostic influence (p=0.008), with no significant influence for age, WBC counts, CD34 expression, or cytogenetics. In turn, a high percentage of early apoptotic cells in bone marrow at diagnosis (p=0.01), as well as a low bcl-2/bax ratio (p=0.05), and low MRP expression (p=0.04) were associated with a prolonged RFS. Moreover, upon grouping AML patients according to the expression of MRP and the bcl-2/bax ratio (> and < of the mean of both parameters), only patients with both low MRP expression and low bcl-2/bax ratio (n=16) achieved a plateau phase in the RFS curve after 20 months of follow-up, while the remaining patients showed a continuous relapse trend. In summary, our results show that, in addition to high bcl-2 and bcl-2/bax ratio, a high expression of the LRP and MRP multidrug resistant proteins have an adverse prognostic influence in elderly AML patients. The combination of these parameters contribute to identify distinct groups of patients at a different risk of relapse.

We have analyzed the results in terms of response rate and peripheral blood progenitor cell (PBPC) mobilization ability of two cisplatin-based chemotherapy salvage regimens [DHAP (cisplatin 100 mg/m2 iv day 1, ara-c 4 g/m2 iv day 2 and dexamethasone 40 mg po days 1-4) and ESHAP (etoposide 40 mg/m2 iv days 1–4, cisplatin 25 mg/m2 iv days 1–4, ara-c 2 g/m2 iv day 5 and methilprednisolone 500 mg iv days 1–5)] in a group of 110 patients with Hodgkin’s lymphoma (HL) in first or subsequent relapses. There were 70 males and 40 females with a median age at diagnosis of 29 years (range, 10 – 79). Sixty seven patients (64%) presented with advanced stage, 54% of them had B symptoms, 32% bulky mediastinal mass and 38%, extranodal disease. Disease status at the time of administration of the salvage protocol was primary refractory disease (PRD) (n = 16, 17%), first relapse (n = 65, 69%), second or subsequent relapse (n = 10, 11%) and relapse after a prior autologous stem cell transplantation (ASCT) (n = 3, 3%). Twenty-seven patients (26%) received the DHAP protocol and the remaining 78 (74%), the ESHAP protocol. Median time from diagnosis to the salvage therapy was 15 (range, 1 – 249) mo. In patients treated after a first relapse, the median duration of the first complete remission (CR) was 7 (range, 1 – 77) mo, with 18% of the patients relapsing after a long first CR (> 12 mo). Median number of cycles administered per patient was 2 (range, 1 – 3) with a median time interval between cycles of 28 (range, 21 – 76) days. PBPCs were collected after the second and the third cycle of chemotherapy in 35% and 49% of the patients respectively and was successful (> 2.0 x 106 CD34+ cells/kg) in 97% of them. Grade 3–4 hematological toxicity was seen in 20% of the cycles with severe neutropenia (< 0.5 x 109/l granulocytes) and thrombocytopenia (< 20 x 109/l platelets) developing in 26% and 7% of the cycles, respectively. The most frequent grade 3–4 extra-hematological toxicity was nausea/vomiting (30%). Procedure related mortality was 2%. Response rate (RR) was 78% [CR: 39%, partial remission (PR): 39%] with significant differences between patients treated for PRD [RR of 41% (CR: 12%, PR: 29%)] and those treated for disease relapse [RR of 86% (CR: 44%, PR: 42%)] (p = 0.005). Cisplatin-based regimens are a useful therapeutical strategy in the treatment of refractory or relapsed HL due to a high overall RR and an adequate PBPC mobilization ability. Results in terms of disease response are significantly worse in patients treated for PRD.

We have analyzed overall survival (OS-REL), progression-free survival (PFS-REL) and the clinical variables influencing the long-term outcome for patients with Hodgkin′s lymphoma (HL) who relapse after an autologous stem cell transplantation (ASCT). From 639 patients autografted for HL [383 males (60%) and 256 (40%) females, median age of 30 (1–66) years] reported to the GEL/TAMO Cooperative Group between January/1984 and January/2003, 175 patients (27%) relapsed at a median time of 10 (4 – 125) months [median (range)] after ASCT. They were 97 males (56%) and 78 (44%) females with a median age of 28 (10 – 66) [median (range)] years at transplantation. Sixty-three patients were autografted in complete remission, 73 in sensitive relapse and 31 in resistant relapse. One hundred and sixty three patients (94%) received different chemotherapy (CT) protocols as conditioning regimen and 12 patients (6%), CT plus total body irradiation. At relapse, 94 patients (53%) presented with advanced stages (III-IV), 49 patients (28%) with B symptoms and 19 (11%) with bulky disease. Relapse was extranodal in 45% of the patient population. Ten percent of the patients had a poor performance status (ECOG ≥2) and 37 patients (22%) had a hemoglobin (Hb) level < 100 g/l at relapse. Thirty four patients (20%) received no further therapy, 107 (60%) received different CT +/− radiotherapy and the remaining 34 patients (20%) were treated with a second stem cell transplantation (13 patients, an ASCT and 21 an allogeneic transplantation). OS-REL and PFS-REL were of 35% ± 4% and 23% ± 4% at 3 years, respectively. Advanced clinical stage (III-IV) at relapse [relative risk (RR) 4.4, 95% confidence interval (CI) (1.7 – 10.8), p = 0.002] and an interval between ASCT and relapse < 12 months [RR 2.4, 95%CI (1.1 – 5.0), p = 0.03] were independent adverse prognostic factors for PFS-REL. Advanced clinical stage at relapse [RR 4.4, 95%CI (1.4 – 14.4), p = 0.012], extranodal disease [RR 2.4, 95%CI (1.3 – 15.4), p = 0.02] and a Hb level < 100 g/l at relapse [RR 3.4, 95%CI (2.0 – 10.4), p = 0.03] were significant adverse prognostic factors for OS-REL. Although the long-term outcome of HL patients who relapse after ASCT is poor, results are better in patients with late relapses and localized disease. Moreover, a minority of the patients can become long-term progression-free survivors after relapse. The identification and construction of prognostic sub-groups according to the number of risk factors may be useful to develop risk-adapted therapeutic strategies.

We have analyzed the incidence and risk factors for developing a secondary malignancy (SM) in patients with Hodgkin’s lymphoma (HL) treated with an autologous stem cell transplantation (ASCT). From 639 patients autografted for HL [383 males and 256 females with a median age of 30 (1–66) years and a median follow-up after ASCT of 53 (3–202) months] reported to the GEL/TAMO Spanish Cooperative Group between January/1984 and January/2003, 37 patients (6% of the series) developed a SM at a median time of 35 months after ASCT [24 patients (65%) a myelodisplastic syndrome (MDS)/acute myelogenous leukemia (AML), 3 patients (8%) a non Hodgkin’s lymphoma (NHL) and 10 patients (29%) a solid tumor (ST)]. There were 24 males and 13 females with a median age of 39 (13–60) years [23 patients (61%), 24 months in 23 patients (62%). Twenty-three patients (62%) were in CR when they developed the SM and the remaining 14 (38%), had active disease. Median time to develop a myeloid malignancy was of 12 (4 – 34) months, to develop a lymphoid malignancy (T cell NHL, 2 patients; B cell NHL, 1 patient) was of 23 (12 – 31) months and to develop a ST (2 squamous cell carcinomas of the lung, 2 rabdomisarcomas, 2 adenocarcinomas of the rectum, 1 basocelular carcinoma, 2 in situ bladder carcinoma and one oropharyngeal carcinoma) of 60 (34 – 91) months, respectively (p = 0.0001). Twenty eight patients have died: 18 patients (64%) due to the SM and 10 (36%) due to HL progression. Multivariate analysis identified age at ASCT > 40 years and the time between diagnosis and ASCT > 24 months as the only two bad prognostic factors for developing a SM [relative risk (RR) 2.48, 95% confidence interval (CI) (1.20–5.10), p = 0.01 and 2.17, 95%CI (1.06–4.46), p = 0.034], respectively. The risk of developing a SM is a real long time side effect after an autologous procedure in HL patients. Advanced age at ASCT and a long time interval between diagnosis and ASCT, a probable surrogate marker of the amount of CT given to the patient before the ASCT have been, in our experience, the only two risk factors for developing this complication.

STI571 (imatinib) is increasingly being used in the treatment of different phases of chronic myeloid leukemia and metastatic gastrointestinal stromal tumors.[1][1],[2][2]Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) has a poor prognosis with the current treatment options.[3][3]

Burkitt's lymphoma (BL) and Burkitt-like acute lymphoblastic leukemia (ALL) are uncommon lymphoproliferative disorders after solid organ or stem cell transplantation. Although their prognosis is considered to be poor, there are scarce data on the clinical characteristics and the response to specific therapies. We report the main clinical characteristics and the results of a specific intensive chemotherapy in 5 adult patients with postransplant BL/ALL3 included in the PETHEMA ALL3/97 protocol. Two patients died in induction, another died in consolidation phase and the remaining 2 patients are in continuous complete remission 6 and 18 months from the diagnosis.

Background and aim: Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance and MRD levels (assessed by cytofluorometry at the end of induction and consolidation therapy) in HR Ph- adult ALL patients. Patients and methods: HR ALL included one or more of the following baseline parameters: age 30–60 yr, WBC count >25x109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy (≥10% blasts in bone marrow assessed on d14) intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level Results: On June 2008,192 patients were evaluable (mean (SD) age 37(10) yr, 105 males, 119 precursor B-ALL, 73 T-ALL, WBC count 65(99) x109/L). Induction death: 17(9%), resistance: 12 (6%), CR: 163 (85%). MRD Conclusions: These results suggest that in HR Ph- adult ALL pts with adequate response to induction and adequate clearance of MDR the results of therapy are not hampered by avoiding allogeneic SCT. Supported by grants P-EF/07 from FIJC and RD 06/0020/1014 from Instituto Carlos III