Lidia Gil

Influence of bone marrow stem cells on left ventricle perfusion and ejection fraction in patients with acute myocardial infarction of anterior wall: randomized clinical trial: Impact of bone marrow stem cell intracoronary infusion on improvement of microcirculation.

AIMS Randomized trial to assess change in left ventricle ejection fraction (LVEF) and myocardial perfusion in patients with acute myocardial infarction (AMI) of anterior wall treated with bone marrow stem cells (BMSCs), compared with control group-from baseline in the acute phase up to 12 months of follow-up. METHODS AND RESULTS Forty-five patients were randomized 2:1 to BMSC group (n= 31) or to control group (n = 14). Bone marrow stem cells were administered into infarct-related artery (IRA) at 4-6 day after primary PCI. Groups were followed up with Tc-99m-MIBI SPECT, radionuclide ventriculography (EF-RNV), echocardiography (ECHO), and spiroergometric stress test. Coronary angiography was repeated after 6 months. EF-RNV did not differ significantly in both groups, but trend towards increase in EF at 6 months and its maintenance after 12 months was noticed in the BMSC group. At rest study, perfusion index (PI) of region supplied with blood by IRA distal to its previous occlusion (PI-IRA) improved significantly in the BMSC group at 6 months: PI-IRA at 4-6 days vs. PI-IRA at 6 months (3.00 +/- 0.97 vs. 2.65 +/- 0.64; P = 0.017). At 12 months, PI-IRA at rest was 2.66 +/- 0.55; P = 0.07. The difference between BMSC and control groups at rest study in PI-IRA was not observed. At dipyridamole study (PI-dip), perfusion in the BMSC group was better compared with controls at 6 months (2.26 +/- 0.44 vs. 2.47 +/- 0.40; P = 0.033) and at 12 months (2.34 +/- 0.55 vs. 2.52 +/- 0.42; P = 0.014), also for region supplied with blood by IRA (PI-IRA-dip; at 6 months 2.63 +/- 0.77 vs. 3.06 +/- 0.46; P = 0.021 and at 12 months 2.71 +/- 0.63 vs. 3.15 +/- 0.51; P = 0.001). Results of LVEF, LVEDV, LVESV in ECHO and results of spiroergometric stress test did not differ significantly between groups. Major adverse cardiac events occurred more often in the control group (P = 0.027). CONCLUSION In our study, BMSC intracoronary transplantation in patients with anterior AMI did not result in increase in EF. Slight improvement of myocardial perfusion was noticed in the BMSC group. This finding may indicate better microcirculation enhanced by BMSCs, but small number of patients allow for hypothesis rather than final statement.

Response to Rituximab-Based Therapy and Risk Factor Analysis in Epstein Barr Virus–Related Lymphoproliferative Disorder After Hematopoietic Stem Cell Transplant in Children and Adults: A Study From the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

BACKGROUND  The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting. METHODS  A total of 4466 allogeneic HSCTs performed between 1999 and 2011 in 19 European Group for Blood and Marrow Transplantation centers were retrospectively analyzed for PTLD, either biopsy-proven or probable disease. RESULTS  One hundred forty-four cases of PTLD were identified, indicating an overall EBV-related PTLD frequency of 3.22%, ranging from 1.16% for matched-family donor, 2.86% for mismatched family donor, 3.97% in matched unrelated donors, and 11.24% in mismatched unrelated donor recipients. In total, 69.4% patients survived PTLD. Multivariable analysis showed that a poor response of PTLD to rituximab was associated with an age ≥30 years, involvement of extralymphoid tissue, acute GVHD, and a lack of reduction of immunosuppression upon PTLD diagnosis. In the prognostic model, the PTLD mortality increased with the increasing number of factors: 0-1, 2, or 3 factors being associated with mortality of 7%, 37%, and 72%, respectively (P < .0001). Immunosuppression tapering was associated with a lower PTLD mortality (16% vs 39%), and a decrease of EBV DNAemia in peripheral blood during therapy was predictive of better survival. CONCLUSIONS  More than two-thirds of patients with EBV-related PTLD survived after rituximab-based treatment. Reduction of immunosuppression was associated with improved outcome, whereas older age, extranodal disease, and acute graft-vs-host disease predicted poor outcome.

Risk of complications during hematopoietic stem cell collection in pediatric sibling donors: a prospective European Group for Blood and Marrow Transplantation Pediatric Diseases Working Party study.

We investigated prospectively factors influencing the safety of hematopoietic stem cell (HSC) collection in 453 pediatric donors. The children in the study donated either BM or peripheral blood stem cells (PBSCs) according to center policy. A large variability in approach to donor issues was observed between the participating centers. Significant differences were observed between BM and PBSC donors regarding pain, blood allotransfusion, duration of hospital stay, and iron supplementation; however, differences between the groups undergoing BM vs PBSC donation preclude direct risk comparisons between the 2 procedures. The most common adverse event was pain, reported mainly by older children after BM harvest, but also observed after central venous catheter (CVC) placement for PBSC collection. With regard to severe adverse events, one patient (0.7%) developed a pneumothorax with hydrothorax after CVC placement for PBSC collection. The risk of allotransfusion after BM harvest was associated with a donor age of < 4 years and a BM harvest volume of > 20 mL/kg. Children < 4 years were at higher risk than older children for allotransfusion after BM harvest and there was a higher risk of complications from CVC placement before apheresis. We conclude that PBSC and BM collection are safe procedures in children.

Increased risk for invasive aspergillosis in patients with lymphoproliferative diseases after autologous hematopoietic SCT

The risk of invasive aspergillosis (IA) is considered to be low among autologous HSCT recipients, but an increase in the incidence has been observed recently in this setting. The aim of the study was to assess the influence of immunosuppressive drugs (steroids, rituximab, fludarabine, thalidomide), used in treatment of lymphoid malignancies during 6 months of pretransplant period, on IA incidence after autologous HSCT. A total of 109 patients with non-Hodgkins lymphoma (NHL), Hodgkins disease (HD) and multiple myeloma (MM), conditioned with carmustine, etoposide, cytarabine, melphalan or melphalan and transplanted with PBSC, were analyzed prospectively. Patients were monitored with twice-weekly galactomannan test. High-resolution computed tomograhy of the chest and bronchoscopy were performed in case of positive galactomanan test, persistent fever or pulmonary infiltrates. Documented IA was diagnosed in nine (8%) patients (three proven, six probable). The incidence of IA was comparable in NHL, HD and MM patients and not influenced by age, advanced disease or conditioning regimen. Factors significant for development of documented IA by univariate analysis were treatment with fludarabine (P=0.008) or rituximab (P=0.039). The only factor predicting documented IA by multivariate analysis was treatment with fludarabine (P=0.008). Patients treated with fludarabine or rituximab in pretransplant period are at risk of IA and require close monitoring and/or anti-mould prophylaxis.

Correlation Between the Kinetics of CD3+ Chimerism and the Incidence of Graft-Versus-Host Disease in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

INTRODUCTION Graft-versus-host disease (GvHD) remains a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT). Early diagnosis and treatment may improve patient outcomes. A prospective study to investigate the relationship between chimerism kinetics and the development of acute or chronic GvHD was carried out. Split chimerism in association with the onset of GvHD was also analyzed. METHODS Thirty-three patients with hematologic diseases treated with allogeneic HSCT were analyzed. They were conditioned with myeloablative or reduced intensity regimens and grafted with peripheral blood (PB) or bone marrow stem cells. GvHD prophylaxis consisted of cyclosporine and methotrexate. Chimerism evaluation was performed on PB mononuclear cells and purified cell subsets consisting of separated CD3(+) T cells, monocytes (CD14(+)), and granulocytes (CD15(+)). Chimerism analysis was performed at 30, 60, 120, and a median of 200 days after HSCT. RESULTS Acute GvHD was diagnosed in 19 patients and chronic GvHD in 16. On day 30, no relation was found between the level of donor chimerism and aGvHD. Upon univariate analysis, decreasing mixed chimerism among CD3(+) and infused CD34(+) cell numbers was significantly correlated with acute GvHD development, while the PB stem cell source, reduced-intensity conditioning regimen, and female donor sex were associated with an increased risk of chronic GvHD. In multivariate analysis, the risk of acute GvHD correlated only with the CD34(+) cell dose, while the risk of extensive chronic GvHD was associated with high CD3(+) donor chimerism on day 30. Patients with versus without split chimerism (T cell vs myeloid lines) did not differ statistically in their incidence of acute GvHD or chronic GvHD. CONCLUSION Our results supported the belief that chimerism kinetics or longitudinal chimerism evaluation is of greater significance than isolated absolute values of the percentage of chimerism at a single point after HSCT. The observations suggest that longitudinal monitoring of chimerism in CD3(+) T-cell subsets is an acceptable method to predict the development of GvHD among patients undergoing HSCT.

Role of Donor Activating KIR–HLA Ligand–Mediated NK Cell Education Status in Control of Malignancy in Hematopoietic Cell Transplant Recipients

Some cancers treated with allogeneic hematopoietic stem cell transplantation (HSCT) are sensitive to natural killer cell (NK) reactivity. NK function depends on activating and inhibitory receptors and is modified by NK education/licensing effect and mediated by coexpression of inhibitory killer-cell immunoglobulin-like receptor (KIR) and its corresponding HLA I ligand. We assessed activating KIR (aKIR)-based HLA I-dependent education capacity in donor NKs in 285 patients with hematological malignancies after HSCT from unrelated donors. We found significantly adverse progression-free survival (PFS) and time to progression (TTP) in patients who received transplant from donors with NKs educated by C1:KIR2DS2/3, C2:KIR2DS1, or Bw4:KIR3DS1 pairs (for PFS: hazard ratio [HR], 1.70; P = .0020, Pcorr = .0039; HR, 1.54; P = .020, Pcorr = .039; HR, 1.51; P = .020, Pcorr = .040; and for TTP: HR, 1.82; P = .049, Pcorr = .096; HR, 1.72; P = .096, Pcorr = .18; and HR, 1.65; P = .11, Pcorr = .20, respectively). Reduced PFS and TTP were significantly dependent on the number of aKIR-based education systems in donors (HR, 1.36; P = .00031, Pcorr = .00062; and HR, 1.43; P = .019, Pcorr = .038). Furthermore, the PFS and TTP were strongly adverse in patients with missing HLA ligand cognate with educating aKIR-HLA pair in donor (HR, 3.25; P = .00022, Pcorr = .00045; and HR, 3.82; P = .027, Pcorr = .054). Together, these data suggest important qualitative and quantitative role of donor NK education via aKIR-cognate HLA ligand pairs in the outcome of HSCT. Avoiding the selection of transplant donors with high numbers of aKIR-HLA-based education systems, especially for recipients with missing cognate ligand, is advisable.

Donor NK cell licensing in control of malignancy in hematopoietic stem cell transplant recipients

Among cancers treated with allogeneic hematopoietic stem‐cell transplantation (HSCT), some are sensitive to natural killer (NK) cell reactivity, described as the “missing self” recognition effect. However, this model disregarded the NK cell licensing effect, which highly increases the NK cell reactivity against tumor and is dependent on the coexpression of inhibitory killer cell immunoglobulin‐like receptor (iKIR) and its corresponding HLA Class I ligand. We assessed clinical data, HLA and donor iKIR genotyping in 283 patients with myelo‐ and lymphoproliferative malignancies who underwent HSCT from unrelated donors. We found dramatically reduced overall survival (OS), progression free survival (PFS), and time to progression (TTP) among patients with malignant diseases with the lack of HLA ligand cognate with this iKIR involved in NK cell licensing in corresponding donor (events 83.3% vs. 39.8%, P = 0.0010; 91.6% vs. 47.7%, P = 0.00010; and 30.0% vs. 17.3%, P = 0.013, for OS, PFS, and TTP, respectively). The extremely adverse PFS have withstand the correction when patient group was restricted to HLA mismatched donor‐recipient pairs. The incidence of aGvHD was comparable in two groups of patients. In malignant patients after HSCT the missing HLA ligand for iKIR involved in NK cell licensing in corresponding donor (“missing licensing proof”) induced extremely adverse survival of the patients due to the progression of malignancy and not to the aGvHD. Avoiding the selection of HSCT donors with the “missing licensing proof” in the malignant patient is strongly advisable.Am. J. Hematol. 89:E176–E183, 2014.

Strategy of pre-emptive management of Epstein-Barr virus post-transplant lymphoproliferative disorder after stem cell transplantation: results of European transplant centers survey.

Aim of the study Epstein-Barr virus-related post-transplant lymphoproliferative disorder (EBV-PTLD) is a serious complication after stem cell transplantation (SCT) and the number of patients at risk is increasing over time. Available data do not reflect general practice of diagnosis and treatment of this complication. Material and methods In 2009 a survey on management of the pre-emptive strategy of EBV infection was done and results from 74 European transplant centers were registered and analyzed. Results Regular monitoring for EBV after SCT is done by most of the participating centers (73%). In 68% of them the monitoring is performed in all alloSCT patients, while in remaining centers it is done in high-risk patients only. Quantitative EBV-DNA is performed in 97% of centers, mainly in whole blood (78%) and usually repeated once a week (60.9%). The monitoring for EBV reactivation is performed for a period of 3 months (37%) to 6 months (30%) or adjusted to risk factors (20%). Rituximab as a pre-emptive therapy for EBV-PTLD is routinely administered in 80% of responding centers. The number of EBV-DNA copies as an indicator for pre-emptive therapy with rituximab varies between the centers. Conclusions The strategy of management of EBV infection exists in most of the responding centers. Different approaches regarding indications for preemptive therapy are seen between centers: rituximab is administered as pre-emptive therapy in most participating transplant centers.

Successful treatment of Epstein-Barr virus-related post-transplant lymphoproliferative disease with central nervous system involvement following allogeneic haematopoietic stem cell transplantation - a case study.

Post-transplant lymphoproliferative disease (PTLD) is a rare but severe form of Epstein-Barr virus (EBV)-driven complication that develops in patients after haematopoietic stem cell transplantation. In rare cases it manifests as primary central nervous system (CNS) involvement, which is thought to be the most unfavourable localisation with respect to outcome. Disease confined to the CNS is much more challenging than systemic PTLD, and one of the contributing factors is the limited drug penetration across the blood-brain barrier. We describe the case of a 29-year-old woman who was successfully treated for PTLD with CNS involvement. The patient was diagnosed with T-cell lymphoblastic lymphoma and underwent the procedure of haematopoietic stem cell transplantation from an unrelated donor. Two months after transplantation she manifested severe headache and progressive mental deterioration accompanied by enlargement of the lymph nodes. Magnetic resonance imaging (MRI) scan revealed segmental, asymmetrical thickening of the meninges. Based on the clinical picture and the laboratory findings diagnosis of PTLD was made. The patient was effectively treated with reduction of immunosuppressive therapy and intravenous rituximab. Initially started intrathecal chemotherapy was stopped due to iatrogenic complications. We conclude that in this case the involvement of meninges in the course of the lymphoproliferative process might have compromised the blood-brain barrier. This factor probably improved rituximabs penetration to CNS, contributing to our patients recovery.

Bendamustine-based therapy as first-line treatment for non-Hodgkin lymphoma

Recently, bendamustine has become an important agent in the treatment for patients with lymphoid malignancies. Although the drug has received approval for second-line therapy in indolent lymphoma, a growing body of evidence suggests its efficacy and safety in first-line use. The results of randomised and observational studies with bendamustine as front-line therapy in non-Hodgkin lymphoma (NHL) with emphasis on efficacy and toxicity are presented. Furthermore, completed and ongoing clinical trials evaluating upfront bendamustine effectiveness in combination with other agents are discussed. The review refers mainly to indolent lymphoma, mantle cell lymphoma and aggressive lymphoma, as the most commonly diagnosed NHL types. Finally, we elaborated on the safety profile of bendamustine and the perspectives of using the drug as a first-line therapy.