Resistance to empirical ß-lactams recommended in febrile neutropenia guidelines in Gram-negative bacilli bloodstream infections in Spain: a multicentre study.

OBJECTIVES: To describe current resistance to the ß-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 ß-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 < 0.001). Thirty day mortality was 14.6%, reaching 21.6% in patients receiving IEAT. CONCLUSIONS: Current resistance to empirical ß-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.

A prognostic model for survival after salvage treatment with FLAG-Ida +/- gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia.

The combination of fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (FLAG-Ida) is widely used in relapsed/refractory acute myeloid leukaemia (AML). We retrospectively analysed the results of 259 adult AML patients treated as first salvage with FLAG-Ida or FLAG-Ida plus Gentuzumab-Ozogamicin (FLAGO-Ida) of the Programa Español de Tratamientos en Hematología (PETHEMA) database, developing a prognostic score system of survival in this setting (SALFLAGE score). Overall, 221 patients received FLAG-Ida and 38 FLAGO-Ida; 92 were older than 60 years. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 51%, with 9% of induction deaths. Three covariates were associated with lower CR/CRi: high-risk cytogenetics and t(8;21) at diagnosis, no previous allogeneic stem cell transplantation (allo-SCT) and relapse-free interval <1 year. Allo-SCT was performed in second CR in 60 patients (23%). The median overall survival (OS) of the entire cohort was 0·7 years, with 22% OS at 5-years. Four independent variables were used to construct the score: cytogenetics, FLT3-internal tandem duplication, length of relapse-free interval and previous allo-SCT. Using this stratification system, three groups were defined: favourable (26% of patients), intermediate (29%) and poor-risk (45%), with an expected 5-year OS of 52%, 26% and 7%, respectively. The SALFLAGE score discriminated a subset of patients with an acceptable long-term outcome using FLAG-Ida/FLAGO-Ida regimen. The results of this retrospective analysis should be validated in independent external cohorts.

Prognostic significance of complex karyotype and monosomal karyotype in adult patients with acute lymphoblastic leukemia treated with risk-adapted protocols.

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.

High Rate of Inappropriate Antibiotics in Patients with Hematologic Malignancies and Pseudomonas aeruginosa Bacteremia following International Guideline Recommendations.

Optimal coverage of Pseudomonas aeruginosa is challenging in febrile neutropenic patients due to a progressive increase in antibiotic resistance worldwide. We aimed to detail current rates of resistance to antibiotics recommended by international guidelines for P. aeruginosa isolated from bloodstream infections (BSI) in patients with hematologic malignancies. Secondarily, we aimed to describe how many patients received inappropriate empirical antibiotic treatment (IEAT) and its impact on mortality. We conducted a retrospective, multicenter cohort study of the last 20 BSI episodes caused by P. aeruginosa in patients with hematologic malignancies from across 14 university hospitals in Spain. Of the 280 patients with hematologic malignancies and BSI caused by P. aeruginosa, 101 (36%) had strains resistant to at least one of the ß-lactam antibiotics recommended in international guidelines, namely, cefepime, piperacillin-tazobactam, and meropenem. Additionally, 21.1% and 11.4% of the strains met criteria for MDR and XDR P. aeruginosa, respectively. Even if international guidelines were followed in most cases, 47 (16.8%) patients received IEAT and 66 (23.6%) received inappropriate ß-lactam empirical antibiotic treatment. Thirty-day mortality was 27.1%. In the multivariate analysis, pulmonary source (OR 2.22, 95% CI 1.14 to 4.34) and IEAT (OR 2.67, 95% CI 1.37 to 5.23) were factors independently associated with increased mortality. We concluded that P. aeruginosa-causing BSI in patients with hematologic malignancies is commonly resistant to antibiotics recommended in international guidelines, which is associated with frequent IEAT and higher mortality. New therapeutic strategies are needed. IMPORTANCE Bloodstream infection (BSI) caused by P. aeruginosa is related with an elevated morbidity and mortality in neutropenic patients. For this reason, optimal antipseudomonal coverage has been the basis of all historical recommendations in the empirical treatment of febrile neutropenia. However, in recent years the emergence of multiple types of antibiotic resistances has posed a challenge in treating infections caused by this microorganism. In our study we postulated that P. aeruginosa-causing BSI in patients with hematologic malignancies is commonly resistant to antibiotics recommended in international guidelines. This observation is associated with frequent IEAT and increased mortality. Consequently, there is a need for a new therapeutic strategy.

Molecular stratification model for prognosis in cytogenetically normal acute myeloid leukemia.

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.

Practice of central nervous system prophylaxis and treatment in acute leukemias in Spain. Prospective registry study.

BACKGROUND AND OBJECTIVE: Central nervous system (CNS) involvement in patients diagnosed with acute leukemias (AL) is an uncommon complication with poor prognosis. The indication and the schedules of prophylaxis and treatment of CNS involvement in AL are not homogenous among countries and within the same country. The aim of this prospective longitudinal study was to analyze and report the practice of CNS prophylaxis and treatment in patients with AL in Spain. PATIENTS AND METHOD: Prospective study conducted from June 2005 to June 2006. Adult patients (> or = 18 yr.) diagnosed with AL who received CNS prophylaxis or treatment were consecutively included through online registration. RESULTS: 265 patients from 32 hospitals were included. Mean (standard deviation) age was 44 (16) yr. and 133 (50%) were males. For acute lymphoblastic leukemia patients (n = 158), CNS therapy was given to 12 cases (10 at diagnosis and 2 at relapse) and consisted of triple intrathecal therapy (TIT, methotrexate, cytarabine and hydrocortisone) in 11 and liposomal depot cytarabine in one. CNS prophylaxis (n = 146) consisted of TIT in 135 cases, intrathecal methotrexate in 7, intrathecal cytarabine in 2 and intrathecal liposomal depot cytarabine in 2. No cranial irradiation either for prophylaxis or therapy was given in any case. In acute myeloblastic leukemia patients (n = 107), CNS therapy was administered to 17 cases (9 at diagnosis and 8 at relapse). Intrathecal therapy consisted of TIT in 11, intrathecal liposomal depot cytarabine in 5 and intrathecal cytarabine in one. One patient also received craniospinal irradiation. CNS prophylaxis (n = 90) consisted of TIT in 68 cases and intrathecal methotrexate in 22. CONCLUSIONS: In Spain, the patterns of CNS prophylaxis and therapy for AL are homogeneous. TIT was the most frequent schedule for CNS prophylaxis and therapy. The lack of use of cranial or craniospinal irradiation and the administration of new drugs (i.e.: liposomal depot cytarabine) for CNS therapy and prophylaxis is of note.

Results of compassionate therapy with intrathecal depot liposomal cytarabine in acute myeloid leukemia meningeosis.

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.

Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia.

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 <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p=0.002). Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p=0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics.

Post-transplant Burkitt's leukemia or lymphoma. Study of five cases treated with specific intensive therapy (PETHEMA ALL-3/97 trial).

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.

Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial.

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.

[Comparison of two initial mobilizing strategies of peripheral blood stem cells for autologous transplantation in patients with lymphoma and human immunodeficiency virus infection]. / Comparación de dos estrategias iniciales de movilización de progenitores hematopoyéticos de sangre periférica para trasplante autogénico en pacientes con linfomas e infección por el virus de la inmunodeficiencia humana.

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. PATIENTS AND METHODS: 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). RESULTS: Between January 2000 and May 2010, 42 patients with lymphoma and HIV infection were referred for ASCT. The rate of successful mobilization (collection >1.60 × 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). CONCLUSIONS: 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.

High FOXO3a expression is associated with a poorer prognosis in AML with normal cytogenetics.

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>50x10(9)/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.

Comparison of the results of the treatment of adolescents and young adults with standard-risk acute lymphoblastic leukemia with the Programa Español de Tratamiento en Hematología pediatric-based protocol ALL-96.

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.

Lack of influence of human immunodeficiency virus infection status in the response to therapy and survival of adult patients with mature B-cell lymphoma or leukemia. Results of the PETHEMA-LAL3/97 study.

BACKGROUND AND OBJECTIVES: 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. DESIGN AND METHODS: 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. RESULTS: 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 age > 60 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 age > 60 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%). Age > 60 years was the only identified factor associated with a shorter DFS (OR 5.2, 95%CI 1.4-20, p=0.015). INTERPRETATION AND CONCLUSIONS: 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.

Comparación de dos estrategias iniciales de movilización de sangre periférica de células madre para el trasplante autólogo en pacientes con linfoma y la infección por virus de inmunodeficiencia humana / Comparison of two initial mobilizing strategies of peripheral blood stem cells for autologous transplantation in patients with lymphoma and human immunodeficiency virus infection

Fundamento y objetivo: Varios estudios han demostrado la viabilidad de trasplante de células madre autólogas (ASCT) en pacientes con linfoma y el virus de la inmunodeficiencia humana (VIH). La infección por VIH se ha descrito como un factor de riesgo para la movilización de los pobres. El objetivo de este estudio fue comparar los resultados de dos estrategias de movilización de las células madre sanguíneas periféricas (CMSP) en pacientes con linfoma y la infección por VIH en siete hospitales españoles. Pacientes y métodos: Las variables recogidas fueron: características demográficas, clínicas y biológicas, quimioterapias anteriores y los resultados, así como las estrategias de movilización de (clasificados en dos grupos: 1) G-CSF, y 2) el G-CSF de quimioterapia +). Resultados: Entre enero de 2000 y mayo de 2010, 42 pacientes con linfoma y la infección por VIH fueron remitidos para ASCT. La tasa de éxito en la movilización (colección> 1,60 × 10 6 células CD34 / kg) con el primer régimen fue del 67%, sin diferencias entre los pacientes movilizados con G-CSF o con G-CSF + quimioterapia (16 [72%] y 12 [60%], respectivamente, p = 0,382). El estado del linfoma en el momento de la movilización fue el único factor para la movilización de éxito (20/22 pacientes [91%] en remisión completa [RC] movilizado adecuadamente frente a 5/12 [58%] en remisión parcial [RP], p = 0,038). Conclusiones: En los pacientes con linfoma y la infección por el VIH, la movilización con G-CSF fue tan eficaz como la movilización con quimioterapia seguida de G-CSF. El estadio de la enfermedad antes de la movilización fue el principal factor de riesgo para el éxito de la movilización, con mejores resultados en los pacientes movilizados en remisión del linfoma (AU)

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. Patients and methods: 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). Results: Between January 2000 and May 2010, 42 patients with lymphoma and HIV infection were referred for ASCT. The rate of successful mobilization (collection >1.60 × 106 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). Conclusions: 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 (AU)

Practice of central nervous system prophylaxis and treatment in acute leukemias in Spain. Prospective registry study

BACKGROUND AND OBJECTIVE: Central nervous system (CNS) involvement in patients diagnosed with acute leukemias(AL) is an uncommon complication with poor prognosis. The indication and the schedules of prophylaxisand treatment of CNS involvement in AL are not homogenous among countries and within the same country.The aim of this prospective longitudinal study was to analyze and report the practice of CNS prophylaxis andtreatment in patients with AL in Spain.PATIENTS AND METHOD: Prospective study conducted from June 2005 to June 2006. Adult patients ( 18 yr.)diagnosed with AL who received CNS prophylaxis or treatment were consecutively included through online registration.RESULTS: 265 patients from 32 hospitals were included. Mean (standard deviation) age was 44 (16) yr. and133 (50%) were males. For acute lymphoblastic leukemia patients (n = 158), CNS therapy was given to 12cases (10 at diagnosis and 2 at relapse) and consisted of triple intrathecal therapy (TIT, methotrexate, cytarabineand hydrocortisone) in 11 and liposomal depot cytarabine in one. CNS prophylaxis (n = 146) consistedof TIT in 135 cases, intrathecal methotrexate in 7, intrathecal cytarabine in 2 and intrathecal liposomal depotcytarabine in 2. No cranial irradiation either for prophylaxis or therapy was given in any case. In acute myeloblasticleukemia patients (n = 107), CNS therapy was administered to 17 cases (9 at diagnosis and 8 at relapse).Intrathecal therapy consisted of TIT in 11, intrathecal liposomal depot cytarabine in 5 and intrathecalcytarabine in one. One patient also received craniospinal irradiation. CNS prophylaxis (n = 90) consisted ofTIT in 68 cases and intrathecal methotrexate in 22.CONCLUSIONS: In Spain, the patterns of CNS prophylaxis and therapy for AL are homogeneous. TIT was the mostfrequent schedule for CNS prophylaxis and therapy. The lack of use of cranial or craniospinal irradiation andthe administration of new drugs (i.e.: liposomal depot cytarabine) for CNS therapy and prophylaxis is of note

FUNDAMENTO Y OBJETIVO: La infiltración del sistema nervioso central (SNC) en pacientes diagnosticados de leucemiaaguda (LA) es una complicación infrecuente que comporta un mal pronóstico. La indicación y las pautasde profilaxis y tratamiento de la infiltración neuromeníngea en la LA no son homogéneas en los diferentes países,y tampoco en los diferentes centros de un mismo país. El objetivo de este estudio longitudinal y prospectivoha sido describir la práctica real de profilaxis y tratamiento de la infiltración neuromeníngea en pacientescon LA en España.PACIENTES Y MÉTODO: Se trata de un estudio prospectivo llevado a cabo desde junio de 2005 a junio de 2006.Se incluyó, mediante registro electrónico, a los pacientes adultos (edad 18 años) diagnosticados de LA querecibieron profilaxis o tratamiento de la infiltración del SNC.RESULTADOS: Se incluyó a un total de 265 pacientes procedentes de 32 hospitales. La media (desviación estándar)de edad fue de 44 (16) años y 133 (50%) eran varones. Entre los 158 pacientes con leucemia linfoblásticaaguda, 12 (10 en el momento del diagnóstico y 2 en recaída) recibieron tratamiento del SNC por infiltraciónneuromeníngea, que consistió en tratamiento intratecal triple (TIT: metotrexato, citarabina e hidrocortisona)en 11 casos y citarabina liposómica de liberación lenta por vía intratecal en uno. La profilaxis del SNC administradaen los 146 pacientes restantes incluyó TIT en 135 casos, metotrexato intratecal en 7, citarabina intratecalen 2 y citarabina liposómica de liberación lenta por vía intratecal en 2. No se administró radioterapiacraneal ni craneoespinal a ningún paciente. Entre los 107 pacientes con leucemia mieloblástica aguda, 17tenían infiltración del SNC (9 en el momento del diagnóstico y 8 en la recaída). El tratamiento intratecal consistióen TIT en 11 casos, citarabina liposómica de liberación lenta en 5 y citarabina intratecal en uno. Unpaciente recibió además radioterapia craneoespinal. La profilaxis del SNC en los 90 pacientes restantes incluyóTIT en 68 casos y metotrexato intratecal en 22.CONCLUSIONES: En España las pautas de profilaxis y tratamiento de la infiltración neuromeníngea en pacientescon LA son homogéneas. El TIT fue el esquema usado con mayor frecuencia tanto para la profilaxis como parael tratamiento del SNC. Llama la atención la escasa utilización de la radioterapia holocraneal o craneoespinal,así como la administración de nuevos fármacos, como la citarabina liposómica de liberación lenta, en el tratamientoy la profilaxis de la meningosis leucémica