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INTRODUCTION: This double-blind, parallel-group, active-controlled phase III trial (NCT02260804) assessed CT-P10 and rituximab safety and efficacy in patients with previously untreated low-tumor-burden follicular lymphoma (LTBFL), including after a single switch from rituximab to CT-P10. PATIENTS AND METHODS: LTBFL patients were randomized (1:1) to receive CT-P10 or rituximab (375 mg/m(2) intravenously; day 1 of 4 7-day cycles). Patients achieving disease control entered a 2-year maintenance period. CT-P10 or rituximab were administered every 8 weeks (6 cycles) in year 1; all patients could receive CT-P10 (every 8 weeks; 6 cycles) in year 2. Secondary endpoints (reported here) were overall response rate (ORR) during the study period, progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Safety and immunogenicity were evaluated. RESULTS: Between November 9, 2015 and January 4, 2018, 258 patients were randomized (130 for CT-P10; 128 for rituximab). ORR was similar between groups over the study period (CT-P10: 88%; rituximab: 87%). After 29.2 months' median follow-up, median PFS, TTP, and OS were not estimable; 24-month Kaplan-Meier estimates suggested similarity between groups. Overall, 114 (CT-P10: 88%), and 104 (rituximab: 81%) patients experienced treatment-emergent adverse events. The single switch was well tolerated. CONCLUSION: These updated data support therapeutic similarity of CT-P10 and rituximab and support the use of CT-P10 monotherapy for previously untreated LTBFL.

Introduction The impact of an admission to ICU before stem cell transplantation (SCT) on post-SCT outcome is not well established. Patients and methods We reviewed the medical records of patients who had received a first SCT between 2000 and 2016 in our institution. The outcome of 22 patients who required ICU admission during chemotherapy prior to SCT (ICU group) was compared with 44 matched patients (1:2) who did not need it (NO-ICU group). Results There were no differences in transplant complications, in time to neutrophil and platelet recovery or in the length of hospital stay during SCT between the ICU and NO-ICU groups. However, microbiologically documented infections were more common in the ICU group (16/20) than in the NO-ICU group (18/39) (p = .027). The 5-yr overall survival probability (CI 95%) was 49% (28–70%) in the ICU vs. 45% (29–61%) in the NO-ICU group (p = .353), while the 5-yr incidence of non-relapse mortality was 32% (14–52%) and 24% (12–38%) (p = .333), respectively. Six patients (27%) in the ICU group and 8 (18%) in the NO-ICU group required admission to the ICU during or after the SCT procedure (p = .293). Twelve (54%) patients in the ICU and 22 (50%) in the NO-ICU group died, the causes of death were similar in both groups. Conclusion Our results show that admission to the ICU prior to SCT does not have a negative impact on patient outcomes following SCT and should not be considered as an exclusion criterion for SCT.

BACKGROUND: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING: Karyopharm Therapeutics Inc.

Background: Relapsed or refractory diffuse large B‑cell lymphoma (RR DLBCL) is an aggressive cancer with a median survival of less than 6 months. The SADAL trial aims to assess the response to the oral selective inhibitor of nuclear export (SINE) selinexor in patients with RR DLBCL who have no therapeutic options of demonstrated clinical benefit. Methods: SADAL was a multicenter, open-label Phase 2b study conducted at 59 sites globally. Patients 18 years with previously treated, pathologically confirmed de novo DLBCL, or DLBCL transformed from previously diagnosed indolent lymphoma, and having received at least two prior therapies were enrolled. Germinal center B-cell (GCB) or non-GCB tumor subtype and double/triple expressor status were determined by immunohistochemistry and double/triple hit status was determined by cytogenetic assays. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The primary outcome was overall response rate (ORR) by central radiologic review. A modified intent-to-treat population was used for all efficacy endpoints. Findings: 127 patients were enrolled from October 21, 2015 through November 2, 2019. The ORR was 28.3% (95% CI: 20.7%, 37.0%), including complete response in 15 (11.8%) and partial response in 21 (16.5%) patients. Median overall survival (OS) was 9.1 months (95% CI: 6.6, 15.1) with longer OS observed in responding patients. Responses were observed across different subgroups regardless of age, gender, prior therapy, DLBCL subtype, refractory status or prior ASCT therapy. Adverse events were generally reversible and managed with dose modifications and/or standard supportive care. Interpretation: In both GCB- and non-GCB DLBCL subtypes, single agent oral selinexor induced durable responses which were associated with longer survival. Selinexor may be a new oral, non-cytotoxic treatment option for patients with RR DLBCL after two lines of chemo-immunotherapy. Trial Registration: This trial is registered at ClinicalTrials.gov, NCT02227251. Funding Statement: This study (NCT02227251) was funded by Karyopharm Therapeutics Inc, Newton, Massachusetts, USA, which provided all study materials. Declaration of Interests: NK reports research support from Verastem, Gilead, Celgene, and Roche, as well as honoraria from Gilead, Janssen, and Karyopharm. FC reports personal fees from Takeda, Gilead, and Janssen, outside the submitted work. MC reports personal fees from Celgene, Gilead, Janssen, Karyopharm, Novartis, Roche, Sandoz, and Servier outside the submitted work. GF reports personal fees from Karyopharm and Roche, outside the submitted work. AG reports personal fees and honoraria from AstraZeneca, personal fees and board membership from Cota and Kite/Gilead, personal fees from Janssen, Celgene, Acerta, and research funding from Constellation, Bayer, CALBG, Genentech, Hoffman-La Roche, MD Anderson, Morphosys, Pharmacyclics, and the University of Nebraska, outside the submitted work. OC reports grants, personal fees, and non-financial support from Roche, personal fees and non-financial support from Takeda, BMS, Amgen, Janssen, Abbvie, grants and personal fees from Gilead, and personal fees from Merck, outside the submitted work. BH reports grants and personal fees from Karyopharm, outside the submitted work. UJ reports personal fees from Karyopharm, during the conduct of the study; grants and personal fees from AbbVie, Celgene, Gilead, Janssen, Novartis, Roche, Takeda, Amgen, Miltenyi, and BMS, outside the submitted work. JMS reports honoraria from Roche, Janssen, Gilead, Celgene, Novartis outside the submitted work. MS reports personal fees from Karyopharm during the conduct of the study, and personal fees from Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Genentech, and Seattle Genetics, outside the submitted work. TPV reports honoraria from WinMedica, Astellas, and Gilead, honoraria, advisory board membership and research support from Takeda, honoraria and advisory board membership from Roche, Bristol, Genesis, and Novartis, advisory board membership at Janssen, honoraria and research support from Merck and Amgen, and research support from Pfizer and Karyopharm. AJ reports personal fees from Karyopharm Therapeutics during the conduct of the study. YL reports personal fees from Karyopharm Therapeutics, outside the submitted work. HC, YL, XM, KC, DM, HW, JS, JRS, SS, and MK are employees of Karyopharm. AJ is a consultant for Karyopharm. MK and SS are stockholders of Karyopharm. SS holds patents (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents (PCT/US12/048319, 499/2012, PI20102724, and 2012000928) on hydrazide-containing nuclear transport modulators and uses. All other authors declare no competing interests. Ethics Approval Statement: The institutional review board or independent ethics committee at each study center approved the protocol, and the study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and the principles of the Declaration of Helsinki.

Background and objective Patients submitted to haematopoietic stem cell transplantation (HSCT) are at increased risk of late complications, such as second neoplasm (SN). The incidence and risk factors of SN in patients receiving HSCT at a single centre were analyzed. Patients and methods The follow-up of adult patients who received a first HSCT (autologous [auto-HSCT] or allogeneic [allo-HSCT]) between January 2000 and December 2015 was reviewed. We collected their demographic characteristics, the primary disease and type of HSCT, and analyzed the cumulative incidence of SN and their risk factors. Results Of 699 transplanted patients (auto-HSCT, n = 451; allo-HSCT, n = 248), 42 (6%) developed SN (17 haematological and 25 solid), 31 post-auto-HSCT and 11 post-allo-HSCT. Haematologic SN were more frequent after auto-HSCT than after allo-HSCT. The median time between HSCT and SN was 4.09 years [range 0.07–13.15], with no differences between auto-HSCT and allo-HSCT. The cumulative incidence of SN was 5% (95% CI 3–6) at 5 years, 7% (95% CI 5–10) at 10 years and 11% (95% CI 8–15) at 15 years, without differences according to the type of HSCT. Only the age over 40 years correlated with an increased risk of SN. Conclusions In this series, the incidence of post-HSCT SN was similar to that previously described. Patients submitted to an auto-HSCT showed a higher frequency of haematologic SN. A higher incidence of SN was detected in patients older than 40 at the time of HSCT.

Resumen Fundamento y objetivo Los receptores de un trasplante de progenitores hematopoyeticos (TPH) tienen un mayor riesgo de complicaciones tardias, como las segundas neoplasias (SN). Se analizo la incidencia de SN en pacientes receptores de un TPH en un centro. Pacientes y metodos Estudio retrospectivo de pacientes adultos receptores de un primer TPH (autogenico [auto-TPH] o alogenico [alo-TPH]) entre enero de 2000 y diciembre de 2015. Se recogieron sus caracteristicas demograficas, la enfermedad de base y el tipo de TPH, y se analizo la incidencia acumulada de SN y sus factores de riesgo. Resultados De 699 pacientes receptores de un auto-TPH (n = 451) o alo-TPH (n = 248), 42 (6%) desarrollaron una SN (17 hematologicas y 25 solidas), 31 postauto-TPH y 11 postalo-TPH. Se observo un mayor numero de SN hematologicas tras auto-TPH que tras alo-TPH. La mediana de tiempo entre el TPH y la SN fue de 4,09 anos [extremos 0,07-13,15], sin diferencias entre auto-TPH y alo-TPH. La incidencia acumulada de SN post-TPH fue de 5% (IC 95% 3-6) a 5 anos, 7% (IC 95% 5-10) a 10 anos y 11% (IC 95% 8-15) a 15 anos, sin diferencias en funcion del tipo de TPH. Solo la edad superior a los 40 anos se correlaciono con un mayor riesgo de SN. Conclusiones En esta serie, la incidencia de SN post-TPH fue similar a la descrita. Los receptores de un auto-TPH presentaron mayor frecuencia de SN hematologicas. Se detecto una mayor incidencia de SN en pacientes de mas de 40 anos en el momento del TPH.

Major floods in Spain in September 9–13, 2019 resulted in seven casualties and massive losses to agriculture, property and infrastructure. This paper investigates the utility of satellite data to: (1) characterize the event when input into a hydrological model, and to provide an accurate picture of the evolution of the floods; and (2) inform meteorologists in real time in order to complement model forecasts. It is shown that the precipitation estimates from the Global Precipitation Measurement (GPM) Core Observatory (GPM-CO, available since 2014) and the merged satellite estimates provide an extraordinary improvement over previous technologies to monitor severe hydrometeorological episodes in near real time. In spite of known biases and errors, these new satellite precipitation estimates can be of broad practical interest to deal with emergencies and long-term readiness, especially for semi-arid areas potentially affected by ongoing global warming. Comparisons of satellite data of the September event with model outputs and more direct observations such as rain gauges and ground radars reinforce the idea that satellites are fundamental for an appropriate management of hydrometeorological events.

Resumen Antecedentes El pronostico de los linfomas difusos de celulas B grandes (LDCBG) transformados de linfomas indolentes (LT) ha sido considerado mas desfavorable que el pronostico de LDCBG de novo . Sin embargo, este parece haber mejorado desde la introduccion de rituximab. Pacientes y metodos Se compararon las caracteristicas (incluyendo la celula de origen) y el pronostico de 29 pacientes con LT y 101 con LDCBG de novo tratados con inmunoquimioterapia. Resultados Los pacientes con LT y LDCBG de novo tenian caracteristicas similares. Todos los casos de LT que evolucionaron de un linfoma folicular fueron linfomas de celulas B de tipo centro germinal, mientras que aquellos LT que evolucionaron de un linfoma de la zona marginal o leucemia linfocitica cronica fueron de tipo no centro germinal. El indice de respuesta completa fue similar en los LT y en los LDCBG de novo (62 frente a 66%, p = 0,825). Las probabilidades de supervivencia global y libre de progresion a 5 anos (IC 95%) fueron del 59% (40-78) y el 41% (22-60) para LT y del 63% (53-73) y el 60% (50-70) para LDCBG de novo , respectivamente (p = 0,732 para supervivencia global y p = 0,169 para supervivencia libre de progresion). Conclusion En este estudio, el pronostico de los LT y LDCBG de novo tratados con inmunoquimioterapia fue similar. El papel de la intensificacion con trasplante de precursores hematopoyeticos en el tratamiento del LT puede ser cuestionable en la era del rituximab.

The prognosis of diffuse large B-cell lymphomas (DLBCL) transformed from indolent lymphoma (TL) has been considered poorer than that of de novo DLBCL. However, it seems to have improved since the introduction of rituximab.We compared the characteristics (including the cell-of-origin), and the prognosis of 29 patients with TL and 101 with de novo DLBCL treated with immunochemotherapy.Patients with TL and de novo DLBCL had similar characteristics. All TL cases evolving from follicular lymphoma were germinal-center B-cell-like, while those TL from marginal zone lymphoma or chronic lymphocytic leukemia were non-germinal-center B-cell-like. The complete response rate was similar in TL and de novo DLBCL (62 vs. 66%, P=.825). The 5-year overall and progression-free survival probabilities (95% CI) were 59% (40-78) and 41% (22-60) for TL and 63% (53-73) and 60% (50-70) for de novo DLBCL, respectively (P=.732 for overall survival and P=.169 for progression-free survival).In this study, the prognosis of TL and de novo DLBCL treated with immunochemotherapy was similar. The role of intensification with stem cell transplantation in the management of TL may be questionable in the rituximab era.

Context: Ibrutinib is a first-in-class oral inhibitor of Bruton's tyrosine kinase, has been established as a standard-of-care (SOC) treatment for R/R MCL. The clinical benefits with ibrutinib has been demonstrated in multiple trials and real-world studies.1-3 Objective: To describe ibrutinib outcomes in real-world patients in Spain. Design: IBRORS is a retrospective multicentre observational study of patients with confirmed diagnosis of R/R MCL who were treated with ibrutinib from January 2016 to March 2019 (6 months prior to the start of the study). The primary end point was PFS. Disease characteristics, previous therapies used, response rates, and survival outcomes with ibrutinib were also evaluated. Patients or other participants: The analysis included 66 evaluable patients from 24 centres in Spain. Median age at diagnosis was 64.5 years (range 57-72), and 78.8% were male. Baseline comorbidities of interest include: hypertension (47%), dyslipidemia (36.4%), and cardiovascular disorders (21.2%). Interventions: Patients had a median of 2 prior lines of therapy (range 1-8). Among the pre-ibrutinib treatments used, the most common treatment was bendamustine plus rituximab in 20.7% of cases, followed by R-CHOP-like combinations in 19.3% and Hyper-CVAD in 16.4%. Results: With a median follow-up of 14.2 months after Ibrutinib initiation, Ibrutinib treatment led to an ORR of 67.8% with a complete response in 24 patients (36.4%) and partial response in 16 patients (24.2%). Median PFS was 20.0 months (95% CI, 8.8-31.1) and median OS was 32 months (95% CI, 22.6-41.3). Adverse events were reported in 43 patients (65.1%). Atrial fibrillation or associated cardiovascular diseases were reported in 2 patients and no major hemorrhages were reported. Conclusions: IBRORS provides information on the first real-world study of ibrutinib use in clinical practice in Spain. The results suggest that ibrutinib is mostly being used in first and second relapses. The data evaluated confirms the favorable adverse event profile and manageability of ibrutinib in real-world clinical practice. References: [1] Wang et al. Blood. 2015; 126:739-745. [2] Wang et al. NEJM. 2013; 369:507-16. [3] Le Gouill et al. EHA 2019, PS1264.

Plasmablastic lymphoma (PBL) is a rare and aggressive subtype of non-Hodgkin lymphoma that commonly occurs in human immunodeficiency virus (HIV)-positive individuals, and affects oral sites. Occasionally, it has been described in HIV-negative patients and involving non-oral sites. Pathologically, PBL is a high-grade B-cell lymphoma that displays the immunophenotype of a terminally differentiated B-lymphocyte with loss of B-cell markers (CD20) and expression of plasma-cell antigens. Epstein-Barr virus infection and MYC rearrangements are frequently observed. Treatment of PBL is challenging because of the lack of established treatment and poor outcomes, with median survival times shorter than one year. In this review, we discuss the clinical and epidemiologic spectrum of PBL as well as its distinct pathological features. Finally, we summarize the currently available approaches for the treatment of patients with PBL.

Resumen Fundamento y objetivo El linfoma de celulas del manto (LCM) es un linfoma poco frecuente, con recaidas habituales y mal pronostico. Este estudio analiza la respuesta al tratamiento y el pronostico en una serie de pacientes con LCM. Pacientes y metodo Estudio retrospectivo de los pacientes con LCM diagnosticados en un centro entre 1996 y 2013. Se dividio la cohorte en funcion del tratamiento recibido. Resultados Se incluyeron 45 pacientes (32 varones) con una edad mediana de 66 anos. Veintiun pacientes recibieron quimioterapia o quimioinmunoterapia intensiva (pautas con citarabina a dosis altas), 13 semiintensiva (sin citarabina a dosis altas), 8 no intensiva y 3 no precisaron tratamiento. La respuesta global fue del 85% con tratamiento intensivo y del 77% con semiintensivo. En el analisis multivariable el tratamiento intensivo se asocio a una mayor probabilidad de supervivencia libre de progresion (SLP) y supervivencia global (SG) (hazard ratio de 9,8 [IC 95% 2,7-35,5], p = 0,001 para la SLP y 4,5 [1,2-17,8], p = 0,03 para la SG). Conclusiones En esta serie retrospectiva de pacientes con LCM el tratamiento intensivo se asocio a mejores resultados respecto al resto de las modalidades de tratamiento.

Central nervous system (CNS) involvement by lymphoma is a complication associated, almost invariably, with a poor prognosis. The knowledge of the risk factors for CNS relapse is important to determine which patients could benefit from prophylaxis. Thus, patients with very aggressive lymphomas (such as lymphoblastic lymphoma or Burkitt's lymphoma) must systematically receive CNS prophylaxis due to a high CNS relapse rate (25–30%), while in patients with indolent lymphoma (such as follicular lymphoma or marginal lymphoma) prophylaxis is unnecessary. However, the question about CNS prophylaxis in patients with diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, remains controversial. The information available is extensive, mainly based on retrospective and heterogeneous studies. There seems that immunochemotherapy based on rituximab reduces the CNS relapse rate. On the other hand, patients with increased serum lactate dehydrogenase plus more than one extranodal involvement seem to have a higher risk of CNS relapse, but a prophylaxis strategy based only on the presence of these 2 factors does not prevent all CNS relapses. Patients with involvement of testes or breast have high risk of CNS relapse and prophylaxis is mandatory. Finally, CNS prophylaxis could be considered in patients with DLBCL and renal or epidural space involvement, as well as in those cases with MYC rearrangements, although additional studies are necessary.

Resumen La infiltracion del sistema nervioso central (SNC) en pacientes con linfoma es una complicacion que se asocia, casi invariablemente, a un pronostico mortal. El conocimiento de los factores de riesgo de dicha infiltracion es fundamental para determinar que pacientes podrian beneficiarse de recibir una profilaxis. Mientras que los pacientes con linfoma muy agresivo (como linfoma linfoblastico y linfoma de Burkitt) deben recibir sistematicamente profilaxis del SNC por su elevado riesgo de recaida neuromeningea (25-30%), los pacientes con linfoma indolente (folicular o marginal, por ejemplo) no la reciben practicamente nunca debido a su bajo riesgo de recaida en el SNC. Sin embargo, existe controversia sobre cuando debe administrarse en pacientes con linfoma B difuso de celula grande (LBDCG), el subtipo mas frecuente de linfoma. La informacion disponible en la bibliografia procede en su mayoria de estudios retrospectivos y heterogeneos. La evidencia parece apoyar la hipotesis de que la inmunoquimioterapia basada en rituximab reduce las recaidas en el SNC. La coexistencia de valores de lactato deshidrogenasa serica elevados junto con mas de una localizacion extraganglionar son factores de riesgo asociados con una mayor frecuencia de recaida neuromeningea, aunque una estrategia basada solo en administrar profilaxis en presencia de ambos factores no previene todas las recaidas. Los pacientes con infiltracion testicular y de mama tienen un elevado riesgo de recaida en el SNC y deben recibir profilaxis. Podria considerarse, asimismo, la profilaxis de la recaida neuromeningea en casos de LBDCG con infiltracion renal o del espacio epidural, o en aquellos que presenten reordenamientos del gen MYC, aunque hacen falta mas estudios que investiguen estos aspectos.

Background: The use of immunochemotherapy has substantially increased the outcome of patients with follicular lymphoma (FL). Nowadays, life expectancy for those reaching a durable response is excellent. Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression-free survival. The aim of this study was to analyze the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age-matched Spanish general population (relative survival; RS). Methods: 263 patients consecutively diagnosed with FL in a 10-year period, needing therapy and treated with rituximab-containing regimens, constituted the training series. An independent cohort of 693 FL patients from the GELTAMO group was used for validation. Findings: In the training cohort, 188 patients (71%) were in complete response at 30 months, with a 10-year overall survival of 53% and 87% for non-CR30 and CR30 patients, respectively. Ten-year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Follicular Lymphoma International Prognostic Index (FLIPI), beta2-microglobulin and response to induction, but not maintenance therapy or PET/CT assessment after induction, predicted RS in the CR30 patients group. FLIPI was the most important variable predicting overall survival in the CR30 group in the multivariate analysis. The impact of CR30 status on RS was validated in the independent GELTAMO series. Interpretation: Follicular lymphoma patients treated with immunochemotherapy who were in complete remission at 30 months showed similar survival to that of the sex- and age-matched Spanish general population. Funding: Instituto de Salud Carlos III, Ministerio de Salud, Espana, Ministerio de Economia y Competitividad, Espana, CIBERONC, the program "Fellowship de Gilead Sciences", Spanish Group of Lymphoma and Bone Marrow Transplantation (GELTAMO). Declaration of Interest: The authors declare no conflicts of interest. Ethical Approval: All the patients gave informed consent to participate in the study according to the declaration of Helsinki and the ethical standards of the Ethic Committee of the Hospital Clinic de Barcelona and in each participating centre in accordance with institutional standards.

Introduction Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, showing a highly variable outcome. In patients with DLBCL relapsed/refractory to first-line treatment with rituximab the usefulness of the revised International Prognostic Index (R-IPI) as a prognostic tool remains unexplored. Some biological parameters (B-cell lymphoma 6 [Bcl-6], Bcl-2, p53, and multiple myeloma 1 [MUM1]) and blood populations (lymphocyte and monocyte counts) have been described as International Prognostic Index-independent prognostic factors. The objective was to evaluate the R-IPI to predict the outcome of DLBCL patients at the time of relapse after a front-line treatment with chemotherapy and rituximab and to establish in this population the relationship between biological parameters and outcome. Patients and Methods We included patients with refractory/relapsed DLBCL after first-line treatment with rituximab-containing regimens; patients must have already finished a rescue treatment also including rituximab. Immunohistochemical assessment of Bcl-2, Bcl-6, p53, and MUM1 expression were undertaken in available biopsies. R-IPI factors were identified from the clinical data at diagnosis and at relapse. Response was assessed using National Cancer Institute-sponsored Working Group guidelines. Results R-IPI prognosis at relapse was not significantly associated with overall response rate (ORR) after Rituximab-chemotherapy rescue therapy. None of the immunohistochemical parameters analyzed correlated with rescue therapy results. In contrast, patients with absolute lymphocyte count (ALC) ≥ 1 × 10 9 /L at relapse were more likely to respond than patients with ALC 9 /L ( P = .05). Conclusion The R-IPI score calculated at relapse could not predict the ORR to second-line treatment. Lymphopenia is a simple and useful predictor for outcome in relapsed/refractory DLBCL and the only prognostic factor that in our hands could predict the overall response to a second-line treatment with rituximab and chemotherapy.

Summary Background No standard first-line systemic treatment for mucosa-associated lymphoid tissue (MALT) lymphoma is available. In a phase 2 study we aimed to assess the safety and activity of a response-adapted combination of bendamustine plus rituximab as upfront treatment for this type of lymphoma. Methods In a multicentre, single-arm, non-randomised, phase 2 trial, we enrolled patients with MALT lymphoma at any site and stage and treated them with bendamustine (90 mg/m 2 on days 1 and 2) plus rituximab (375 mg/m 2 on day 1), every 4 weeks. Inclusion criteria were measurable or evaluable disease, age 18–85 years, and unequivocal active lymphoma; we also enrolled patients with MALT lymphoma arising in the stomach after failure of Helicobacter pylori eradication and primary cutaneous cases after failure of local therapies. Exclusion criteria included evidence of histological transformation, CNS involvement, and active hepatitis B or C virus or HIV infection. After three cycles, patients achieving complete response received one additional cycle (total four cycles) and those achieving partial response received three additional cycles (total six cycles). The primary endpoint was 2-year event-free survival. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01015248. Findings 60 patients from 19 centres in Spain were enrolled between May 27, 2009, and May 23, 2011, and received treatment; 57 patients were evaluable for the primary endpoint. Only 14 (25%) patients needed more than four cycles of treatment. After a median follow-up of 43 months (IQR 37–51), median event-free survival was not reached. Event-free survival at 2 years was 93% (95% CI 84–97) and at 4 years was 88% (95% CI 74–95). The most frequently observed grade 3–4 adverse events were haematological: lymphopenia in 20 (33%) patients, neutropenia in 12 (20%) patients, and leucopenia in three (5%) patients. Grade 3–4 febrile neutropenia or infections were reported in three (5%) and four (7%) patients, respectively. Interpretation This response-adapted schedule of bendamustine plus rituximab appears to be an active and well tolerated first-line treatment for patients with MALT lymphoma. Funding Grupo Espanol de Linfomas/Trasplante de Medula Osea (GELTAMO), Mundipharma Spain, and Roche Pharma Spain.

Background aims The increasing scarcity of young related donors has led to the use of older donors for related allogeneic hematopoietic stem cell transplantation (HSCT). This study analyzed the influence of age on the results of mobilization of peripheral blood stem cells (PBSCs) in healthy donors as well as on the engraftment and outcome of HSCT. Methods A retrospective analysis from a single center was performed comparing the results of PBSC mobilization from related healthy donors according to their age. Results The study included 133 consecutive related donors. The median age was 50 years (range, 4–77 years); 70 (53%) donors were males, and 44 (33%) were >55 years old. All donors were mobilized with granulocyte colony-stimulating factor for 5 days. The peak CD34 + cell count in peripheral blood was higher in younger than in older donors (median, 90.5 CD34 + cells/μL [range, 18–240 CD34 + cells/μL] versus 72 CD34 + cells/μL [range, 20–172.5 CD34 + cells/μL], P = 0.008). The volume processed was lower in younger than in older donors (16,131 mL [range, 4424–36,906 mL] versus 18,653 mL [range, 10,003–26,261 mL], P = 0.002) with similar CD34 + cells collected (579.3 × 10 6 cells [range, 135.14 × 10 6 –1557.24 × 10 6 cells] versus 513.69 × 10 6 cells [range, 149.81 × 10 6 –1290 × 10 6 cells], P = 0.844). There were no differences in time to recovery of neutrophils and platelets or in the incidences of acute and chronic graft-versus-host disease, overall survival, non-relapse mortality and relapse incidence. Conclusions Donors >55 years old mobilized fewer CD34 + cells and required a greater volume to collect a similar number of CD34 + cells. The outcome of HSCT was not influenced by donor age. Donor age should not be a limitation for related allogeneic HSCT.

In a recent paper, Navi et al. [(1)][1] showed that patients with cancer have an increased risk of myocardial infarction and ischemic stroke in the months after the cancer diagnosis. The study included almost 280,000 pairs of cancer (8 types, including non-Hodgkin lymphoma [NHL]) and matched

Failure in mobilization of peripheral blood (PB) stem cells is a frequent reason for not performing hematopoietic stem cell transplantation (HSCT). Early identification of poor mobilizers could avoid repeated attempts at mobilization, with the administration of pre-emptive rescue mobilization.Data from the first mobilization schedule of 397 patients referred consecutively for autologous HSCT between 2000 and 2010 were collected. Poor mobilization was defined as the collection of2 × 10(6) CD34(+)cells/kg body weight (BW).The median age was 53 years (range 4-70) and 228 (57%) were males. Diagnoses were multiple myeloma in 133 cases, non-Hodgkin's lymphoma in 114, acute myeloid leukemia or myelodysplastic syndrome in 81, Hodgkin's lymphoma in 42, solid tumors in 17 and acute lymphoblastic leukemia in 10. The mobilization regimen consisted of recombinant human granulocyte-colony-stimulating factor (G-CSF) in 346 patients (87%) and chemotherapy followed by G-CSF (C + G-CSF) in 51 (13%). Poor mobilization occurred in 105 patients (29%), without differences according to mobilization schedule. Diagnosis, previous therapy with purine analogs and three or more previous chemotherapy lines were predictive factors for poor mobilization. A CD34(+)cell count in PB13.8/μL was enough to ensure ≥ 2 × 10(6) CD34(+)cells/kg, with high sensitivity (90%) and specificity (91%).The prevalence of poor mobilization was high, being associated with disease type, therapy with purine analogs and multiple chemotherapy regimens. The threshold of CD34(+) cell count in PB identified poor mobilizers, in whom the administration of immediate or pre-emptive plerixafor could be useful to avoid a second mobilization.

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.

Bendamustine is a alkylating agent with a purine-like benzamidazole ring currently approved in Europe for indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. Our aim was to analyze retrospectively the efficacy and toxicity of bendamustine in NHL and CLL in Spain in the bendamustine Compassionate Use Program. Patients with relapsed/refractory NHL or CLL were eligible. Any regimen containing bendamustine was eligible. 109 patients were included from 22 institutions. Forty-nine patients had indolent NHL, 18 aggressive NHL and 42 CLL, being 44 patients (40%) refractory to previous treatment. 63% of patients had adverse events grade 3-4, mainly hematological. Overall response rate (ORR) was 66%, complete responses 30%. ORR observed in refractory patients was 45%. The median progression-free survival (PFS) was 13 months. Outcome was influenced by histology, number of previous treatments, resistance to previous chemotherapy and type of response achieved with bendamustine. Alone or in combination, bendamustine shows a meaningful clinical antitumor activity in patients with relapsed or refractory NHL or CLL, with an acceptable toxicity profile.

Resumen Fundamento y objetivo El uso creciente de tratamientos antineoplasicos ha provocado un aumento de la incidencia de leucemias agudas secundarias (LAS). El objetivo de este trabajo fue describir las caracteristicas de las LAS en un solo centro. Pacientes y metodo Se registraron 23 casos de LAS. Se analizaron los agentes citotoxicos utilizados, tiempo hasta el diagnostico, caracteristicas clinico-biologicas, tratamiento y pronostico. Resultados La edad mediana fue de 61 anos. Los agentes administrados en la neoplasia previa fueron: alquilantes (17 pacientes), inhibidores de la DNA topoisomerasa II (14), antitubulina (12), radioterapia (9, en 6 con quimioterapia) y antimetabolitos (6). La mediana de tiempo hasta la aparicion de la LAS fue 3 anos (extremos 1,2-15,8). Trece pacientes recibieron quimioterapia intensiva (3 se consolidaron con un trasplante de progenitores hematopoyeticos [TPH]) mientras que los 10 restantes recibieron tratamiento de soporte (mediana de supervivencia de 3 anos frente a 0,079 anos, p = 0,004). Conclusiones En este estudio, la LAS se asocio con la exposicion de agentes alquilantes, inhibidores de la topoisomerasa II y agentes antitubulina. La respuesta al tratamiento y el pronostico fueron malos, aunque la quimioterapia y el TPH podrian proporcionar una supervivencia mas prolongada.

Resumen Fundamento y objetivo La doxorrubicina liposomal no pegilada provoca menor toxicidad cardiaca que la doxorrubicina convencional, por lo que se ha empleado en pacientes de edad avanzada o con cardiopatias. El objetivo de este estudio fue valorar la eficacia y la seguridad de quimioterapias que incluyen doxorrubicina liposomal no pegilada en pacientes diagnosticados de linfoma no hodgkiniano (LNH). Pacientes y metodo Estudio retrospectivo de pacientes con LNH tratados con doxorrubicina liposomal en 2 hospitales. Se recogieron las caracteristicas demograficas, clinicas y biologicas, asi como el tratamiento, la respuesta y la toxicidad. Resultados Se incluyeron 26 pacientes, de los que 15 (58%) eran mujeres. La mediana de edad fue de 76 anos (extremos: 42–86). El tipo de LNH mas frecuente fue el B difuso de celula grande (20 casos). Diecinueve pacientes (73%) se hallaban en estadio iii o iv y 12 (57%) de los 21 pacientes con linfoma B difuso de celula grande y linfoma folicular grado 3 tenian un Indice Pronostico Internacional de alto riesgo. Tres pacientes (12%) presentaban una fraccion de eyeccion inferior al 50% previa al tratamiento. El factor de riesgo cardiovascular mas prevalente fue la hipertension arterial (50%) y 6 pacientes (23%) presentaban antecedentes de cardiopatia. Todos recibieron doxorrubicina liposomal no pegilada como parte de la pauta R-COMP (rituximab, ciclofosfamida, vincristina, doxorrubicina liposomal y prednisona), en 20 casos (77%) tras el diagnostico y en los 6 restantes como segunda linea. Dos pacientes fallecieron tras la administracion del primer ciclo (uno por muerte subita y otro por progresion). De los 18 pacientes tratados en primera linea, 11 (61%) pacientes alcanzaron la respuesta completa, 5 (28%) pacientes alcanzaron la respuesta parcial y 2 (11%) pacientes progresaron. De los 6 pacientes tratados tras la recaida, un paciente alcanzo la respuesta completa, 3 pacientes alcanzaron la respuesta parcial y 2 pacientes progresaron. Once pacientes (46%) presentaron neutropenia de grado iii / iv , 10 pacientes (42%) presentaron neutropenia febril y un paciente (4%) presento trombocitopenia de grado iv . La mediana de supervivencia global fue de 50,7 meses (intervalo de confianza del 95%: 8–93,3) y la de supervivencia libre de enfermedad fue de 18,4 meses (intervalo de confianza del 95%: 18,1–18,7). Conclusiones En esta serie de pacientes, la mayoria de edad avanzada y con factores de riesgo cardiovascular, el tratamiento con doxorrubicina liposomal no pegilada como parte de la pauta R-COMP ha demostrado ser eficaz. La toxicidad observada fue aceptable.

Fundamento y objetivo Aunque cada vez son mas numerosas las indicaciones del trasplante de progenitores hematopoyeticos (TPH), este no siempre llega a efectuarse. El objetivo de este estudio ha sido analizar las causas por las que no se realiza el TPH en los enfermos remitidos a una unidad de trasplante. Pacientes y metodo Se registraron los datos correspondientes a la visita pretrasplante efectuada a 129 enfermos remitidos de forma consecutiva a una unidad de trasplante hematopoyetico entre diciembre de 1999 y noviembre de 2002 y se analizaron la frecuencia y las causas de falta de realizacion del TPH. Por ultimo, se compararon las caracteristicas de los pacientes trasplantados y no trasplantados. Resultados De los 129 pacientes, 119 fueron remitidos para la realizacion de un trasplante autogenico y 10 para un TPH alogenico. La edad media (DE) era de 46 (14) anos (intervalo, 13–69 anos) y 69 pacientes (53,5%) eran varones. Ciento dieciocho tenian hemopatias malignas y 11 tumores solidos. Sesenta y un enfermos se hallaban en respuesta completa y 68 en respuesta parcial. Hasta el momento del analisis se habian realizado 93 TPH en 90 pacientes (69,8%). Ochenta y un pacientes recibieron un TPH autogenico (un paciente recibio un doble TPH) y 10, un TPH alogenico (dos en un paciente). Dos pacientes (1,5%) permanecen en lista de espera para realizar un trasplante autogenico. En 37 pacientes (28,7%) no se llego a efectuar el TPH. Las causas incluyeron: recaida o progresion de la enfermedad en el tiempo en el que se planeo realizar el TPH en 12 (32,5%), aplazamiento o cambio en la decision terapeutica en 12 (32,5%), movilizacion insuficiente de progenitores hematopoyeticos en 9 (24%) y rechazo del TPH por parte del paciente en 4 (11%). Si se excluye el aplazamiento, la frecuencia de falta de realizacion del TPH fue del 19,4%. De los 37 pacientes en los que no se realizo el TPH, se habia efectuado previamente la recoleccion de progenitores hematopoyeticos a 21 (57%). Ambos grupos (trasplantados y no trasplantados) fueron comparables para las principales caracteristicas, excepto la edad, que fue significativamente mayor en el grupo de pacientes no trasplantados (51 [12] frente a 44 [14] anos; p Conclusiones En una proporcion significativa de pacientes el TPH programado no llega a realizarse. Las causas mas frecuentes son la progresion de la enfermedad y la mala movilizacion de progenitores hematopoyeticos. Un motivo adicional para no realizar el TPH es el aplazamiento de la indicacion, ya sea programado o bien debido a la aparicion de nuevas estrategias terapeuticas.

Fundamento y objetivo: Diversos grupos han aprovechado la quimioterapia de rescate en linfomas en recaida o quimiorresistentes para efectuar una movilizacion de progenitores hematopoyeticos de sangre periferica. El objetivo de este estudio ha sido evaluar la eficacia y la toxicidad de una pauta movilizadora de progenitores hematopoyeticos de sangre periferica con altas dosis de ifosfamida, etoposido, metilprednisolona (IFOVM) y factor estimulador de colonias de granulocitos (G-CSF). Pacientes y metodo: Se realizaron 24 procedimientos de movilizacion en pacientes con linfoma, con la pauta IFOVM y G-CSF. La edad mediana fue de 45 anos y 13 eran varones. Los subtipos histologicos fueron: difuso de celulas grandes B (LBDCG) (n = 15), de Hodgkin (n = 2), de Burkitt (n = 2), de celulas del manto (n = 2), anaplasico (n = 1), T periferico (n = 1) y folicular (n = 1). Resultados: Dos pacientes fallecieron por sepsis en el periodo de aplasia y 17 (77%) de los restantes movilizaron mas de 1,5 3 106 celulas CD34+/kg (mediana: 7,7 3 106 celulas CD34+/kg). La aferesis se llevo a cabo el dia 17 desde el inicio de la quimioterapia y en 4 pacientes fue preciso realizar 2 aferesis. Dieciseis pacientes (67%) presentaron neutropenia febril. La mediana de tiempo hasta alcanzar una cifra de neutrofilos superior a 1,0 3 109/l y de plaquetas mayor de 20 3 109/l fue de 15 y 16 dias, respectivamente. El unico factor predictivo de movilizacion satisfactoria fue el diagnostico de LBDCG (p = 0,04). Se efectuo trasplante autogenico de progenitores hematopoyeticos a 10 de los 17 pacientes que movilizaron. Conclusiones: La pauta IFOVM y G-CSF produjo una movilizacion eficaz en los pacientes con linfoma, sobre todo LBDCG, aunque la toxicidad fue elevada

Fundamento y objetivo La frecuencia y la causa de las complicaciones neurologicas (CN) despues de un trasplante de progenitores hemopoyeticos (TPH) son muy variables y han ido cambiando con el tiempo. Se analizan las CN en una serie de 185 TPH consecutivos efectuados en un solo centro durante un periodo de 5 anos. Pacientes y metodo Entre febrero de 2000 y marzo de 2005 se realizaron 185 TPH (44 alogenicos), por diferentes hemopatias malignas, de las cuales las mas frecuentes fueron el mieloma multiple (41 casos) y la leucemia mieloblastica aguda (n = 35). De cada paciente con CN se recogieron las variables demograficas, las caracteristicas del TPH y las caracteristicas clinicas, etiologia, tratamiento y evolucion de las CN. En todos los casos con CN se llevo a cabo una prueba de imagen (tomografia computarizada y/o resonancia magnetica), asi como un estudio microbiologico del liquido cefalorraquideo. Resultados Tras una mediana de seguimiento de 27 meses, un 14 de los pacientes (7,5%) sufrieron CN (6 tras un TPH alogenico). La pauta de acondicionamiento mas utilizada fue BEAM (carmustina, etoposido, citarabina y mefalan) (5/14), y en 6 pacientes la profilaxis de la enfermedad del injerto contra el huesped se realizo con ciclosporina y metotrexato. Recibieron metotrexato intratecal 3 pacientes. La mediana de aparicion de la CN fue de 13 dias desde el TPH (extremos: −4 y + 135) y la manifestacion clinica mas frecuente fue la convulsion (8 casos), seguida de la encefalopatia (3 casos). En 12 pacientes la causa de la CN fue farmacologica, en uno una encefalitis viral y en el restante una hemorragia. Fallecieron 2 pacientes, uno por purpura trombotica trombocitopenica atribuida a ciclosporina y el segundo por encefalitis viral. Conclusiones En esta serie la mayoria de las CN del TPH fueron inducidas por farmacos, lo que contrasta con otras series historicas en las que la infeccion, sobre todo fungica, fue la principal causa. Este hecho debe tenerse en cuenta a la hora de efectuar el diagnostico.

The recommended treatment of grade 3 (or grade 3B) follicular lymphoma patients is that of diffuse large B-cell lymphoma rather than that of follicular lymphoma. These recommendations are not supported by randomized evidence. While RCHOP is a good therapeutic option for both follicular lymphoma and diffuse large B-cell lymphoma, the advent of targeted therapies is likely to change the optimal first-line regimen in both of these entities or, at least, some subset of patients. If that becomes the case, the current consensus-based (rather than evidence-based) approach to grade 3 follicular lymphoma will become a clinical concern to which we are, at present, unable to provide a satisfactory solution.

Resumen Fundamento y objetivo El fracaso de movilizacion de progenitores hematopoyeticos a sangre periferica (celulas CD34 + ) desde el compartimento medular es una causa frecuente de no realizacion de trasplante autogenico de progenitores hematopoyeticos (TAPH) en pacientes con linfoma o mieloma. Plerixafor, un inhibidor reversible de la union del factor derivado del estroma 1 con su receptor CXCR4, ha demostrado mayor movilizacion de progenitores hematopoyeticos cuando se administra junto con granulocyte colony stimulating factor (G-CSF, «factor estimulante de colonias granulociticas»), respecto a la movilizacion con G-CSF solo, por lo que en la actualidad esta indicado en pacientes con mieloma o linfoma y escasa capacidad de movilizacion. En los ultimos anos algunos estudios han senalado que una estrategia de administracion anticipada de plerixafor durante la primera movilizacion, basada en el numero de celulas CD34 + movilizadas a sangre periferica o en la celularidad obtenida en la primera aferesis, podria evitar fracasos de movilizacion y nuevas movilizaciones, asi como el retraso del ulterior trasplante. El objetivo del presente consenso fue realizar una revision de la bibliografia y establecer unas recomendaciones comunes para hospitales de Cataluna y Baleares para la utilizacion de una estrategia de administracion anticipada de plerixafor. Metodos Para la elaboracion del documento de consenso se realizaron reuniones presenciales en las que se realizo una revision de la bibliografia y de datos propios procedentes de los hospitales participantes. Para calificar el grado de la evidencia disponible y establecer las recomendaciones de uso anticipado de plerixafor se ha utilizado el sistema GRADE. Resultados y conclusiones Tras la revision de la bibliografia, el consenso de expertos definio que con un recuento inferior a 10 celulas CD34 + /μl en sangre periferica (determinado en la manana del dia cuarto de la movilizacion con G-CSF solo o en el dia de la recuperacion hemoperiferica tras la movilizacion con quimioterapia seguida de G-CSF) se recomienda la administracion anticipada de plerixafor.

Fundamento Valorar la promocion de la donacion desangre realizada en el entorno de los pacientes quereciben un trasplante de progenitores hematopoyeticos(TPH) y compararla con la promocion que se realizaen el entorno del resto de pacientes ingresados. Pacientes y metodo El hematologo y el promotor delBanco de Sangre informaron de la probabilidad detransfusion al paciente candidato a TPH. Se efectuouna seleccion de los posibles donantes para ladonacion de sangre total o de plaquetas. En el restode los pacientes ingresados la promocion se efectuomediante la visita del promotor al paciente transfundidoo con solicitud de transfusion, sin intervenciondel medico que atendia al paciente. Resultados Entre enero de 2000 y mayo de 2001se realizaron 48 visitas a pacientes candidatos aTPH: 41 (85%) aportaron 453 posibles donantes,306 donaron sangre, 77 plaquetas y 82 fueron excluidos.Se obtuvieron 484 donaciones, 389 desangre total y 105 de plaquetas. Un 25% (98 donantes)volvio a donar espontaneamente. Entre elresto de los pacientes ingresados, durante el ano1998 se realizaron 1.950 entrevistas, consiguiendocolaboracion en 533 (27,3%) de los casos (p Conclusiones La implicacion del hematologo en lapromocion de la donacion a partir del entorno de lospacientes ingresados repercute en un aumento de latasa de donaciones y en la fidelidad de las mismas.