Efficacy and safety of autologous haematopoietic stem cell transplantation versus alemtuzumab, ocrelizumab, ofatumumab or cladribine in relapsing remitting multiple sclerosis (StarMS): protocol for a randomised controlled trial.

INTRODUCTION: Autologous haematopoietic stem cell transplantation (aHSCT) is increasingly used as treatment for patients with active multiple sclerosis (MS), typically after failure of disease-modifying therapies (DMTs). A recent phase III trial, 'Multiple Sclerosis International Stem Cell Transplant, MIST', showed that aHSCT resulted in prolonged time to disability progression compared with DMTs in patients with relapsing remitting MS (RRMS). However, the MIST trial did not include many of the current high-efficacy DMTs (alemtuzumab, ocrelizumab, ofatumumab or cladribine) in use in the UK within the control arm, which are now offered to patients with rapidly evolving severe MS (RES-MS) who are treatment naïve. There remain, therefore, unanswered questions about the relative efficacy and safety of aHSCT over these high-efficacy DMTs in these patient groups. The StarMS trial (Autologous Stem Cell Transplantation versus Alemtuzumab, Ocrelizumab, Ofatumumab or Cladribine in Relapsing Remitting Multiple Sclerosis) will assess the efficacy, safety and long-term impact of aHSCT compared with high-efficacy DMTs in patients with highly active RRMS despite the use of standard DMTs or in patients with treatment naïve RES-MS. METHODS AND ANALYSIS: StarMS is a multicentre parallel-group rater-blinded randomised controlled trial with two arms. A total of 198 participants will be recruited from 19 regional neurology secondary care centres in the UK. Participants will be randomly allocated to the aHSCT arm or DMT arm in a 1:1 ratio. Participants will remain in the study for 2 years with follow-up visits at 3, 6, 9, 12, 18 and 24 months postrandomisation. The primary outcome is the proportion of patients who achieve 'no evidence of disease activity' during the 2-year postrandomisation follow-up period in an intention to treat analysis. Secondary outcomes include efficacy, safety, cost-effectiveness and immune reconstitution of aHSCT and the four high-efficacy DMTs. ETHICS AND DISSEMINATION: The study was approved by the Yorkshire and Humber-Leeds West Research Ethics Committee (20/YH/0061). Participants will provide written informed consent prior to any study specific procedures. The study results will be submitted to a peer-reviewed journal and abstracts will be submitted to relevant national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN88667898.

Impact of exergames on bmi and cardiovascular risk factors: a systematic review / Impacto de exergames sobre imc y los factores de riesgo cardiovascular: revisión sistemática / Impacto de exergames no imc e fatores de risco cardiovascular: uma revisão sistemática

ABSTRACT Introduction: Exergames or active video games are digital platforms with functionality associated with body movement, which dialogue with improving physical activity levels, stimulating pleasure in practice and adherence to change habits, physically active behavior, and better quality of life. Objective: This study aimed to synthesize the available evidence on the contribution of exergame to Body Mass Index, physical activity level, glycemic control, blood pressure, and cardiorespiratory fitness in adolescents. Methods: This is a systematic review, reported following the PRISMA writing recommendations, without language restrictions, for articles indexed in the following databases: MEDLINE / PubMed, Embase, Cochrane Library, and Lilacs. Data extraction was performed analogously in a spreadsheet previously tested and standardized. The assessment of the risk of bias in the included studies was carried out by the RoB 1.0 tool in all of its domains in duplicate of reviewers. Initially, 3.039 studies were found. Results: The studies cover a total of 526 adolescents aged ten to 19. The most used platform in the studies was the Nintendo Wii, followed by the PlayStation, Xbox 360, and Dance Dance Revolution. The results indicated that interventions using exergames were effective for changing BMI, but there was no evidence on cardiovascular outcomes, with no effective changes in glycemic control and blood pressure and a significant response (p <0.05) in cardiorespiratory fitness. Conclusion: The exergame points to satisfactory results in improving health and can be incorporated as a relevant public policy in the adolescent health promotion. (PROSPERO Registration CRD42020181772). Level of evidence II; Therapeutic studies - investigation of treatment results.

RESUMEN Introducción: Los Exergames o videojuegos activos son plataformas digitales con funcionalidad asociada al movimiento corporal, que dialogan con la mejora de los niveles de actividad física, estimulando el placer en la práctica y la adherencia a cambios de hábitos, conducta físicamente activa y mejor calidad de vida. Objetivo: Este estudio tuvo como objetivo sintetizar la evidencia disponible sobre la contribución del exergame al índice de masa corporal, nivel de actividad física, control glucémico, presión arterial y aptitud cardiorrespiratoria en adolescentes. Métodos: Se trata de una revisión sistemática, reportada siguiendo las recomendaciones de redacción de PRISMA, sin restricción de idioma, para artículos indexados en las siguientes bases de datos: MEDLINE / PubMed, Embase, Cochrane Library y Lilacs. La extracción de datos se realizó de manera similar en una hoja de cálculo estandarizada y probada previamente. La evaluación del riesgo de sesgo en los estudios incluidos se realizó mediante la herramienta RoB 1.0 en todos sus dominios por duplicado de revisores. Inicialmente, se encontraron 3.039 estudios. Resultados: Los estudios abarcaron un total de 526 adolescentes de 10 a 19 años. La plataforma más utilizada en estudios fue la Nintendo Wii, seguida de la PlayStation, Xbox 360 y Dance Dance Revolution. Los resultados indicaron que las intervenciones con exergames fueron efectivas para cambiar el IMC, pero no hubo evidencia sobre los resultados cardiovasculares, no hubo cambios efectivos en el control glucémico y la presión arterial, y una respuesta explicativa (p <0.05) en la aptitud cardiorrespiratoria. Conclusión: El exergame muestra resultados satisfactorios en la mejora de la salud y puede ser incorporado como una política pública relevante en la promoción de la salud de los adolescentes. (Registro PROSPERO CRD42020181772). Nivel de evidencia II; Estudios terapéuticos: investigación de los resultados del tratamiento.

RESUMO Introdução: Exergames ou vídeo games ativos são plataformas digitais com funcionalidade associada ao movimento corporal, que dialogam com a melhora dos níveis de atividade física, estimulando o prazer na prática e a adesão à mudança de hábitos, comportamento ativo e melhor qualidade de vida. Objetivo: Este estudo teve como objetivo sintetizar as evidências disponíveis sobre a contribuição do exergame para o Índice de Massa Corporal, nível de atividade física, controle glicêmico, pressão arterial e aptidão cardiorrespiratória em adolescentes. Métodos: Trata-se de uma revisão sistemática, relatada seguindo as recomendações de redação do PRISMA, sem restrição de idioma, para artigos indexados nas seguintes bases de dados: MEDLINE / PubMed, Embase, Cochrane Library e Lilacs. A extração dos dados foi realizada de forma análoga em planilha previamente testada e padronizada. A avaliação do risco de viés nos estudos incluídos foi realizada pela ferramenta RoB 1.0 em todos os seus domínios em duplicata de revisores. Inicialmente, foram encontrados 3.039 estudos. Resultados: Os estudos abrangeram um total de 526 adolescentes de dez a 19 anos. A plataforma mais utilizada nos estudos foi o Nintendo Wii, seguido do PlayStation, Xbox 360 e Dance Dance Revolution. Os resultados indicaram que as intervenções com exergames foram eficazes para alterar o IMC, mas não houve evidências sobre os desfechos cardiovasculares, sem alterações eficazes no controle glicêmico e na pressão arterial e uma resposta significativa (p <0,05) na aptidão cardiorrespiratória. Conclusão: O exergame aponta resultados satisfatórios na melhoria da saúde e pode ser incorporado como uma política pública relevante na promoção da saúde do adolescente. (Registro PROSPERO CRD42020181772). Nível de evidência II; Estudos terapêuticos: investigação dos resultados do tratamento.

Prepubertal oral exposure to relevant doses of acrylamide impairs the testicular antioxidant system in adulthood, increasing protein carbonylation and lipid peroxidation.

The increased prevalence of human infertility due to male reproductive disorders has been linked to extensive exposure to chemical endocrine disruptors. Acrylamide (AA) is a compound formed spontaneously during the thermal processing of some foods that are mainly consumed by children and adolescents. We previously found that prepubertal exposure to AA causes reduced sperm production and functionality. Oxidative stress is recognized as the main cause of reduced sperm quality and quantity. In this sense, our objective was to evaluate the expression and activity of genes related to enzymatic antioxidant defense, nonprotein thiols, lipid peroxidation (LPO), protein carbonylation (PC) and DNA damage in the testes of rats exposed to acrylamide (2.5 or 5 mg/kg) from weaning to adult life by gavage. For the AA2.5 and AA5 groups, there were no alterations in the transcript expression of genes related to enzymatic antioxidant defense. The enzymatic activities and metabolic parameters were also not affected in the AA2.5 group. For the AA5 group, the enzymatic activities of G6PDH and GPX were reduced, SOD was increased, and protein carbonylation (PC) was increased. Data were also evaluated by Integrate Biomarker Response (IBRv2), a method to analyze and summarize the effects on biomarkers between doses. The IBRv2 index was calculated as 8.9 and 18.71 for AA2.5 and AA5, respectively. The following biomarkers were affected by AA2.5: decreased enzymatic activities of G6PDH, SOD, and GPX, increased GST and GSH, increased LPO and PC, and decreased DNA damage. For AA5, decreased enzymatic activities of G6PDH, GST, CAT and GPX, increased SOD and GSH, increased PC, and decreased LPO and DNA damage were observed. In conclusion, AA exposure during the prepubertal period causes imbalances in the testicular enzymatic antioxidant defense, contributing to the altered spermatic scenario in the testes of these rats.

Autologous Hematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: A Real-world Case Series.

OBJECTIVE: To examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting. METHODS: This was a retrospective cohort study of PwMS treated with AHSCT at 2 centers in London, UK, consecutively between 2012 and 2019 who had ≥6 months of follow-up or died at any time. Primary outcomes were survival free of multiple sclerosis (MS) relapses, MRI new lesions, and worsening of Expanded Disability Status Scale (EDSS) score. Adverse events rates were also examined. RESULTS: The cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS. At baseline, the median EDSS score was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85 months). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of participants at 2 years and in 85% at 4 years. EDSS score progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. Epstein-Barr virus reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplantation-related deaths within 100 days (2.5%), all after fluid overload and cardiac or respiratory failure. CONCLUSIONS: Efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher. CLASSIFICATION OF EVIDENCE: This study is rated Class IV because of the uncontrolled, open-label design.

Treinamento resistido modula TNF-α e melhora força muscular de pessoas vivendo com HIV e em tratamento de Terapia Antirretroviral de Alta Atividade / Resistance training modulates TNF-α and improves muscle strength in people living with HIV taking Highly Active Antiretroviral Therapy

O estudo tem como objetivo avaliar a contribuição do treinamento resistido em marcadores de es-tresse oxidativo e força de pessoas vivendo com HIV. Trata-se de um ensaio clínico não randomizado, com delineamento de série temporal descontinua, e amostragem por voluntários pertencentes ao Programa de Atenção Municipal às DST/HIV/AIDS (PAMDHA) com tratamento de Terapia Antirretroviral de Alta Atividade. Foram realizadas avaliações de composição corporal, aptidão física, dano oxidativo e enzimas antioxidantes. Nas variáveis antropométricas entre homens foi encontrada diferenças entre os grupos nos valores de circunferência abdominal (pré = 93,95 ± 8,21; pós = 92,25 ± 7,46) e percentual de gordura (pré = 88,5 ± 6,35; pós = 18,57 ± 7,74). Os níveis de força indicaram melhora em ambos os grupos (p < 0,05). As análises de grupamentos Carbonila, da atividade da enzima antioxidante Catalase, Superóxido Dismutase (SOD), substâncias reativas ao ácido tiobarbi-túrico - Thiobarbituric acid reactive substances (TBARS) e os níveis de TNF-α no soro de indivíduos HIV+, não apresentaram diferenças significativas (p < 0,05). Os resultados demonstraram que o treinamento resistido de intensidade moderada pode ser utilizado como agente terapêutico adjunto ao uso da TARV para a manutenção e melhora da saúde de pessoas com HIV

The study aims to evaluate the contribution of resistance training in oxidative stress and strength markers of people living with HIV. This is a non-randomized clinical trial, with a discontinuous time series design, and sampling by volunteers belonging to the Municipal Care Program for STD/HIV/AIDS (PAMDHA) with High Activity Antiretroviral Therapy treatment. Body composition, physical fitness, oxidative damage and antioxidant enzymes were evaluated. In the anthropometric variables among men, differences were found between the groups in the values of waist circumference (pre = 93.95 ± 8.21; post = 92.25 ± 7.46) and fat percentage (pre = 88.5 ± 6.35; post = 18.57 ± 7.74). Strength levels indicated improvement in both groups (p < 0.05). The analysis of carbonyl groups, the activity of the antioxidant enzyme Catalase, Superoxide Dismutase (SOD), Thiobarbituric acid reactive substances (TBARS) and the levels of TNF-α in serum preferentially HIV+, did not differ significantly (p < 0.05). The results showed that moderate-intensity resistance training can be used as an adjunct therapeutic agent to the use of ART for the maintenance and improvement of the health of people with HIV

Preclinical toxicology and safety pharmacology of the first-in-class GADD45ß/MKK7 inhibitor and clinical candidate, DTP3.

Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)ß/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)ß/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo, ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers.

HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation.

A cure for HIV-1 remains unattainable as only one case has been reported, a decade ago1,2. The individual-who is known as the 'Berlin patient'-underwent two allogeneic haematopoietic stem-cell transplantation (HSCT) procedures using a donor with a homozygous mutation in the HIV coreceptor CCR5 (CCR5Δ32/Δ32) to treat his acute myeloid leukaemia. Total body irradiation was given with each HSCT. Notably, it is unclear which treatment or patient parameters contributed to this case of long-term HIV remission. Here we show that HIV-1 remission may be possible with a less aggressive and toxic approach. An adult infected with HIV-1 underwent allogeneic HSCT for Hodgkin's lymphoma using cells from a CCR5Δ32/Δ32 donor. He experienced mild gut graft-versus-host disease. Antiretroviral therapy was interrupted 16 months after transplantation. HIV-1 remission has been maintained over a further 18 months. Plasma HIV-1 RNA has been undetectable at less than one copy per millilitre along with undetectable HIV-1 DNA in peripheral CD4 T lymphocytes. Quantitative viral outgrowth assays from peripheral CD4 T lymphocytes show no reactivatable virus using a total of 24 million resting CD4 T cells. CCR5-tropic, but not CXCR4-tropic, viruses were identified in HIV-1 DNA from CD4 T cells of the patient before the transplant. CD4 T cells isolated from peripheral blood after transplantation did not express CCR5 and were susceptible only to CXCR4-tropic virus ex vivo. HIV-1 Gag-specific CD4 and CD8 T cell responses were lost after transplantation, whereas cytomegalovirus-specific responses were detectable. Similarly, HIV-1-specific antibodies and avidities fell to levels comparable to those in the Berlin patient following transplantation. Although at 18 months after the interruption of treatment it is premature to conclude that this patient has been cured, these data suggest that a single allogeneic HSCT with homozygous CCR5Δ32 donor cells may be sufficient to achieve HIV-1 remission with reduced intensity conditioning and no irradiation, and the findings provide further support for the development of HIV-1 remission strategies based on preventing CCR5 expression.

Impact of route and adequacy of nutritional intake on outcomes of allogeneic haematopoietic cell transplantation for haematologic malignancies.

BACKGROUND: Allogeneic haematopoietic cell transplantation (HCT) is often associated with poor oral intake due to painful mucositis and gastrointestinal sequalae that occur following a preparative regimen of intensive chemotherapy and/or total body radiation. Although attractive to assume that optimal nutrition improves HCT outcomes, there are limited data to support this. It is also unclear whether artificial nutrition support should be provided as enteral tube feeding or parenteral nutrition (PN). METHODS: We analysed day-100 non-relapse mortality (NRM), incidence of acute graft-versus-host disease (GvHD), acute gastrointestinal GvHD, 5-year survival and GvHD-free/relapse-free survival (GRFS) according to both route and adequacy of nutritional intake prior to neutrophil engraftment, together with other known prognostic factors, in a retrospective cohort of 484 patients who underwent allogeneic HCT for haematologic malignancy between 2000 and 2014. RESULTS: Multivariate analyses showed increased NRM with inadequate nutrition (hazard ratio (HR) 4.1; 95% confidence interval (CI) 2.2-7.2) and adequate PN (HR 2.9; 95% CI 1.6-5.4) compared to adequate enteral nutrition (EN) both P < .001. There were increased incidences of gastrointestinal GvHD of any stage and all GvHD ≥ grade 2 in patients who received PN (odds ratio (OR) 2.0; 95% CI 1.2-3.3; P = .006, and OR 1.8; 95% CI 1.1-3.0; P = .018, respectively), compared to adequate EN. Patients who received adequate PN and inadequate nutrition also had reduced probabilities of survival and GRFS at 5 years. CONCLUSION: Adequate EN during the early transplantation course is associated with reduced NRM, improved survival and GRFS at 5 years. Furthermore, adequate EN is associated with lower incidence of overall and gut acute GvHD than PN, perhaps because of its ability to maintain mucosal integrity, modulate the immune response to intensive chemo/radiotherapy and support the gastrointestinal tract environment, including gut microflora.

Serum-free light chains in HIV-associated lymphoma: no correlation with histology or prognosis.

OBJECTIVES: Serum-free light chains (sFLCs) are a biomarker of B-cell proliferation. Two case-control studies found elevated levels of polyclonal sFLCs predict the development of HIV-associated lymphomas (HALs) in people living with HIV. This effect appears greater for non-Hodgkin's lymphomas than Hodgkin's lymphoma. In this study, we measured sFLCs at diagnosis of HALs, and correlated levels with histology and survival. METHODS: The clinic database of the National Centre for HIV Malignancy was used to identify HAL patients, in the antiretroviral treatment era. Levels of sFLCs were measured using stored sera (cases from 1996 to 2008) and prospectively from 2008 to 2014. Serum immunoglobulins were available for 201 patients. We assessed correlations between sFLCs, serum immunoglobulins, and histological subtypes and overall survival. RESULTS: Two hundred and sixty-four patients were identified and 70% had polyclonal sFLC, 8% monoclonal sFLC (90% kappa sFLC), and 22% normal sFLC levels. No significant difference in sFLCs was observed between the three major histological subtypes of HAL (Hodgkin's lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma). Elevated sFLCs did not influence overall survival in HAL or for the three subtypes individually. DISCUSSION: Whilst these data confirm the finding of elevated sFLC in HAL, there was no significant difference in sFLC measurements between histological subtypes despite differences in pathogenesis. sFLC did not predict survival in HAL overall or by histological subtype. Elevated sFLCs may predict HAL, but measurement of sFLCs has limited utility in the classification and prognostication of these cases.

Tyrosine kinase inhibitors impair B-cell immune responses in CML through off-target inhibition of kinases important for cell signaling.

Tyrosine kinase inhibitors (TKIs) have significant off-target multikinase inhibitory effects. We aimed to study the impact of TKIs on the in vivo B-cell response to vaccination. Cellular and humoral responses to influenza and pneumococcal vaccines were evaluated in 51 chronic phase chronic myeloid leukemia (CML) patients on imatinib, or second-line dasatinib and nilotinib, and 24 controls. Following vaccination, CML patients on TKI had significant impairment of IgM humoral response to pneumococcus compared with controls (IgM titer 79.0 vs 200 U/mL, P = .0006), associated with significantly lower frequencies of peripheral blood IgM memory B cells. To elucidate whether CML itself or treatment with TKI was responsible for the impaired humoral response, we assessed memory B-cell subsets in paired samples collected before and after imatinib therapy. Treatment with imatinib was associated with significant reductions in IgM memory B cells. In vitro coincubation of B cells with plasma from CML patients on TKI or with imatinib, dasatinib, or nilotinib induced significant and dose-dependent inhibition of Bruton's tyrosine kinase and indirectly its downstream substrate, phospholipase-C-γ2, both important in B-cell signaling and survival. These data indicate that TKIs, through off-target inhibition of kinases important in B-cell signaling, reduce memory B-cell frequencies and induce significant impairment of B-cell responses in CML.

European data on stem cell mobilization with plerixafor in patients with nonhematologic diseases: an analysis of the European consortium of stem cell mobilization.

BACKGROUND: Plerixafor with granulocyte-colony-stimulating factor (G-CSF) has been shown to enhance stem cell mobilization in patients with multiple myeloma and lymphoma with previous mobilization failure. In this European named patient program we report the experience in insufficiently mobilizing patients diagnosed with nonhematologic diseases. STUDY DESIGN AND METHODS: Thirty-three patients with germ cell tumor (n=11), Ewing sarcoma (n=6), Wiscott-Aldrich disease (n=5), neuroblastoma (n=4), and other nonhematologic diseases (n=7) were included in the study. Plerixafor was limited to patients with previous or current stem cell mobilization failure and given after 4 days of G-CSF (n=21) or after chemotherapy and G-CSF (n=12) in patients who mobilized poorly. RESULTS: Overall, 28 (85%) patients succeeded in collecting at least 2×10(6)/kg body weight (b.w.) CD34+ cells (median, 5.0×10(6)/kg b.w. CD34+ cells; range, 2.0×10(6)-29.5×10(6)/kg b.w. CD34+ cells), and five (15%) patients collected a median of 1.5×10(6)/kg b.w. CD34+ cells (range, 0.9×10(6)-1.8×10(6)/kg b.w. CD34+ cells). Nineteen patients proceeded to transplantation. The median dose of CD34+ cells infused was 3.3×10(6)/kg b.w. (range, 2.3×10(6)-6.7×10(6)/kg b.w. CD34+ cells). The median numbers of days to neutrophil and platelet engraftment were 11 (range, 9-12) and 15 (range, 10-25) days, respectively. CONCLUSION: These data emphasize the role of plerixafor in combination with G-CSF or chemotherapy and G-CSF as an effective mobilization regimen with the potential of successful stem cell collection. Accordingly, plerixafor seems to be safe and effective in patients with nonhematologic diseases. Larger prospective studies are warranted to further assess its use in these patients.

Plerixafor for autologous peripheral blood stem cell mobilization in patients previously treated with fludarabine or lenalidomide.

Fludarabine and lenalidomide are essential drugs in the front-line treatment of non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), respectively. Data suggests that fludarabine and lenalidomide therapy may have a deleterious effect on stem cell mobilization. In the European compassionate use program, 48 patients (median age 57 years) previously treated with fludarabine (median 5 cycles; range: 1-7 cycles) were given plerixafor plus granulocyte colony-stimulating factor (G-CSF) for remobilization following a primary mobilization attempt. The overall median number of CD34+ cells collected was 2.3 × 10(6)/kg (range: 0.3-13.4). The minimum required number of CD34+ cells (≥2.0 × 10(6)/kg) was collected from 58% of patients in a median of 2 days. Thirty-five patients (median age = 57 years) previously treated with lenalidomide (median 5 cycles; range: 1-10 cycles) were given plerixafor plus G-CSF for remobilization. The overall median number of CD34+ cells collected was 3.4 × 10(6)/kg (range: 1.1-14.8). The minimum required number of CD34+ cells (≥2.0 × 10(6) per kg) was collected from 69% of patients in a median of 2 days. In conclusion, salvage mobilization with plerixafor plus G-CSF is successful in the majority of patients with MM previously treated with lenalidomide. In fludarabine-exposed patients, only 58% of patients will achieve successful salvage mobilization with plerixafor plus G-CSF, suggesting the need for novel mobilization regimens algorithms in this subgroup of patients.

EBMT risk score predicts outcome of allogeneic hematopoietic stem cell transplantation in patients who have failed a previous transplantation procedure.

Increasing numbers of allogeneic hematopoietic stem cell transplantation (allo-SCT) are being performed for patients who have failed a previous allogeneic or autologous SCT. We investigated whether the EBMT risk score could predict outcome after a subsequent allo-SCT. We analyzed prognostic factors in 124 consecutive patients who underwent a second transplantation using an allogeneic donor at our institution. Patients with either a first autologous (N = 64) or first allogeneic (N = 60) SCT were included. Age, disease stage, time interval from diagnosis to transplantation, donor type, and donor-recipient sex combination were used to establish a score from 0 to 7 points, from which 3 groups were identified. The 5-year survival probability decreased from 51.7% for risk scores 0-3 (low, n = 25), to 29.3% for risk score 4 (intermediate, n = 42), and only 10.4% for risk scores 5-7 (high, n = 57), P = .001. We propose that the EBMT risk score can identify patients most likely to benefit from a second transplantation.

Repeated vaccination is required to optimize seroprotection against H1N1 in the immunocompromised host.

BACKGROUND: In 2009 the declaration by the World Health Organization of a global pandemic of influenza-H1N1 virus led to a vaccination campaign to ensure protection for immunocompromised patients. The goal of this study was to determine the efficacy of the 2009 H1N1 vaccine in patients with hematologic malignancies. DESIGN AND METHODS: We evaluated humoral and cellular immune responses to 2009 H1N1 vaccine in 97 adults with hematologic malignancies and compared these responses with those in 25 adult controls. Patients received two injections of vaccine 21 days apart and the controls received one dose. Antibody titers were measured using a hemagglutination-inhibition assay on days 0, 21 and 49 after injection of the first dose. Cellular immune responses to H1N1 were determined on days 0 and 49. RESULTS: By day 21 post-vaccination, protective antibody titers of 1:32 or more were seen in 100% of controls compared to 39% of patients with B-cell malignancies (P<0.001), 46% of allogeneic stem cell transplant recipients (P<0.001) and 85% of patients with chronic myeloid leukemia (P=0.086). After a second dose, seroprotection rates increased to 68%, (P=0.008), 73%, (P=0.031), and 95% (P=0.5) in patients with B-cell malignancies, after allogeneic stem cell transplantation and with chronic myeloid leukemia, respectively. On the other hand, T-cell responses to H1N1 vaccine were not significantly different between patients and controls. CONCLUSIONS: These data demonstrate the efficacy of H1N1 vaccine in most patients with hematologic malignancies and support the recommendation for the administration of two doses of vaccine in immunocompromised patients. These results may contribute towards the development of evidence-based guidelines for influenza vaccination in such patients in the future.

Humoral and cellular immunity to primary H1N1 infection in patients with hematologic malignancies following stem cell transplantation.

Limited data are available on immunologic responses to primary H1N1 infection in patients with hematologic malignancies. We present a prospective, case-surveillance study of such patients with real-time polymerase chain reaction (RT-PCR) confirmed H1N1-influenza who presented to our institution between September 2009 and January 2010. Ninety-two patients presented with influenza-like symptoms, and 13 had H1N1 infection confirmed by RT-PCR, including 4 allogeneic stem cell transplant recipients (1 with acute myelogenous leukemia, 1 with chronic lymphoblastic leukemia [CLL], 1 with non-Hodgkin lymphoma, and 1 with chronic myelogenous leukemia), 5 patients with multiple myeloma following autologous stem cell transplantation, 1 patient with multiple myeloma perimobilization, 2 patients with NHL post chemotherapy, and 1 patient with CLL. All 13 patients required hospitalization. Six (43%) were admitted to the intensive care unit (ICU), of whom 4 (67%) died. We evaluated B cell and T cell responses to H1N1 infection prospectively in these patients compared with those in 4 otherwise healthy controls. Within 12 weeks of diagnosis, only 6 of 11 patients developed seropositive antibody titers as measured by hemagglutination-inhibition or microneutralization assays, compared with 4 of 4 controls. H1N1-specific T cells were detected in only 2 of 8 evaluable patients compared with 4 of 4 controls. H1N1-specific T cells were functional, capable of producing interferon γ, tumor necrosis factor α, and CD107a mobilization. Furthermore, CD154 was up-regulated on CD4(+) T cells in 3 of 4 controls and 2 of 2 patients who had both B cell and T cell responses to H1N1. Post-H1N1 infection, 5 of 8 patients developed seasonal influenza-specific T cells, suggesting cross-reactivity induced by H1N1 infection. These data offer novel insights into humoral and cell-mediated immunologic responses to primary H1N1 infection.