European Group For Bone Marrow Transplantation Research Articles

The Prognostic Impact of the Donor/Recipient CMV Serostatus in Patients with Different Chronic Hematological Disorders after Allogeneic Hematopoietic Stem Cell Transplantation: A Report from the Infectious Diseases Working Party of EBMT

IntroductionCytomegalovirus (CMV) seropositivity of the recipient and/or the donor is still associated with a major overall survival (OS) decline in acute leukemia patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) despite the fact that the incidence of CMV disease has markedly been reduced by preemptive treatment of CMV infection. However, CMV infection after allo-HSCT might also have a favourable effect by reducing the relapse incidence (RI), at least in acute myeloid leukemia. Less is known about the prognostic impact of the CMV serostatus in patients with different chronic hematological disorders undergoing allo-HSCT.MethodsWe analyzed the prognostic impact of the CMV serostatus in a large cohort of 6968 patients who underwent allo-HSCT between the year 2005 and the year 2016 and who were documented in the database of the European Bone Marrow Transplantation Group. Patients with the following diseases were included: Myelodysplastic syndrome (n=2326), multiple myeloma (n=1788), myeloproliferative neoplasm other than Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) (n=979), follicular lymphoma (n=673), Ph+ CML (n=458), mantle cell lymphoma (n=433) and B cell chronic lymphocytic leukemia (n=311). The primary endpoint was 2-year progression-free survival (PFS) of patients with CMV seronegativity of both the donor and the recipient vs the remaining patients.ResultsThe analysis encompassed 2026 patients (29%) with CMV seronegativity of both the donor and the recipient, 2510 patients (36%) with CMV seropositivity of both of them in addition to 815 (12%) and 1617 patients (23%) with CMV seropositivity only of the donor or the recipient, respectively.Patients with CMV seronegativity of both the donor and the recipient had a significantly superior 2-year PFS (52.5%) compared to patients with CMV seropositivity of the donor and/or the recipient (49.5%, p=0.03). In addition, 2-year OS was significantly shorter for patients with CMV seropositivity of the donor and/or the recipient (62.3%) than for those cases with CMV seronegativity of both of them (65.4%, p=0.01). The negative prognostic impact of CMV seropositivity of the donor and/or the recipient remained in a multivariate Cox regression analysis including other important variables (e.g., T cell depletion, donor type) with a significantly reduced PFS (HR 1.09, 95% CI 1.01-1.17, p=0.03) and OS (HR 1.13, 95% CI 1.04-1.23, p=0.003).CMV-seropositive patients allografted from a CMV-seronegative donor showed a particular unfavorable OS compared to patients with CMV seronegativity of both of them (HR 1.21, 95% CI 1.10-1.34) whereas OS was only slightly reduced in patients with CMV seropositivity of only the donor (HR 1.03, 95% CI 0.91-1.17) or of both of them (HR 1.07, 95% CI 0.98-1.17) (p=0.001). Patients with CMV seropositivity of the donor and/or the recipient further showed a significantly increased non-relapse mortality (NRM) in a multivariate Cox regression analysis (HR 1.15, 95% CI 1.03-1.28, p=0.02). CMV-seropositive patients with a CMV-seronegative donor had the highest NRM (HR 1.22, 95% CI 1.07-1.39), followed by CMV-seropositive recipients with CMV-seropositive donors (HR 1.05, 95% CI 0.93-1.19) and finally CMV-seronegative recipients with CMV-seropositive donors (HR 0.99, 95% CI 0.83-1.18) (p=0.01).The donor/recipient CMV serostatus had no significant impact on acute or chronic graft- vs -host disease, donor/recipient hematopoietic chimerism or RI. Interaction analyses revealed that there are not relevant differences on the prognostic impact of the CMV serostatus among different underlying diseases and donor types.ConclusionsOur data show that the CMV serostatus still has a significant prognostic impact in patients with different chronic hematological disorders undergoing allo-HSCT, despite the implementation of sophisticated antiviral strategies in recent years. CMV-seronegative donors should be avoided whenever possible for CMV-seropositive recipients whereas a CMV-seropositive donor might be adequate for a CMV-seronegative recipient. The fact that CMV seropositivity of the donor and/or the recipient - as the most important risk factor for CMV infection - had no significant impact on the RI argues against a clinically relevant 'virus vs malignancy´ effect in these disorders. DisclosuresSocié:Alexion Pharmaceuticals, Inc.: Consultancy. Lamy:Roche: Consultancy, Honoraria.

Conquest of COVID-19. Publish it to death?

Conquest of COVID-19. Publish it to death?

Perspective: Cell therapy, SARS-CoV-2, COVID-19, and James Lind.

Perspective: Cell therapy, SARS-CoV-2, COVID-19, and James Lind.

Impact of Amotosalen/UVA Pathogen Inactivated Platelet Components on Outcomes after Allogeneic Hematopoetic Stem Cell Transplantation: A Single Center Analysis

Background: Platelet component (PC) transfusion is required for allogeneic hematopoietic stem cell transplantation (HCT) recipients. Contamination with infectious pathogens (bacteria, viruses, or protozoa) and T-cells is a risk factor for transfusion-transmitted infection (TTI) and transfusion associated graft-versus-host disease (TA-GVHD). Pathogen inactivation (PI) treatment of PC with amotosalen-UVA (PI-PC, INTERCEPT Blood System, Cerus Corp) in platelet additive solution (PAS) without bacterial screening, gamma irradiation, CMV serology, and with 7-day storage has been the standard of care in Switzerland since 2011 to manage risk of TTI and TA-GVHD. PI-PC have replaced conventional PC (C-PC) prepared in PAS with gamma irradiation and 5 day storage. We previously reported platelet usage in two consecutive five year periods at the University Hospital of Basel. Mean PI-PC dose was higher (3.0 vs. 2.8 x 1011, p=0.001) and mean storage duration longer (4.2 vs. 3.4 days: p=0.001) than with C-PC. PC expiration wastage was reduced with 7-day PI-PC storage vs. 5-day storage (1.5% vs. 8.7%). For HCT recipients, days of PC support; PC use per patient; and RBC use per patient were similar, despite 24.3% lower corrected count increments (CCI) with PI-PC. Now, we report the impact of these observations on treatment related mortality (TRM) and overall survival (OS) 100 days after HCT. Patients and Methods: A two-period retrospective cohort study was conducted to evaluate PI-PC impact on outcomes of consecutive first allogeneic HCT recipients from January 2006 to December 2010 (Period 1, P1), when gamma-irradiated apheresis C-PC were used, and Period 2 (P2) from January 2011 to December 2017, when apheresis and whole blood-derived PI-PC were used. The review utilized 100-day OS and 100-day TRM to determine the impact of PI-PC on HCT outcomes. Descriptive statistics were used for continuous variables and log-rank analysis for survival outcomes. Univariate analysis was performed using Pearson χ2 statistics. Multivariate Cox regression modelling analyses included: PC period (P1, P2), donor match (HLA identical/twin, matched related, matched unrelated), disease state (early, intermediate, late), and conditioning regimen (reduced intensity, myeloablative) with TRM as the outcome. This was an IRB approved single-center analysis. Results: In P1 and P2, 256 and 557 consecutive first-time allogeneic HCT recipients were included, respectively. By univariate analysis, the distribution of European Group for Bone Marrow Transplantation (EBMT) risk scores (grouped 0-2, 3-4, 5-7) and mean patient age were higher during P2 (p = 0.001 and p <0.001, respectively). Primary disease status (p = 0.039); stem cell source (p <0.001); GVHD prophylaxis with ATG (p <0.001); total body irradiation (p <0.001); and conditioning regimen (p <0.001) were different between P1 and P2. Donor match (p=0.084) and disease status (p = 0.628) were similar in P1 and P2. TRM at day 100 post HCT was significantly less (31/557, 5.5%) for PI-PC recipients in P2 vs. C-PC recipients in P1 (37/256, 14.5%, p<0.001). Overall proportion of survivors at day 100 post HCT was significantly greater for PI-PC recipients (507/557, 91.0 %) compared to C-PC recipients (209/256, 81.6%, p <0.001). By multivariate Cox regression analysis, P2 with PI-PC component support was associated with improved TRM (p = 0.001; adjusted hazard ratio 0.433; 95% confidence interval: 0.262, 0.716). Donor match (p = 0.019), disease state (p = 0.022), and myeloablative conditioning (p = 0.034) were associated with significantly poorer TRM (Table). Stem cell source was not significant (p=0.157) in the model. Hemorrhage was reported as cause of death in 1/50 (2.0%) patients during P2 with PI-PC and 4/47 (8.5%) patients during P1 with C-PCs. Conclusions: Universal implementation of PI-PC in routine with extended storage to 7 days in P2 was associated with reduced TRM and better overall survival 100 days post HCT, despite transplantation of older patients with higher EBMT risk scores. Multivariate analysis revealed an adjusted hazard ratio of 0.433 (95% C.I. 0.262, 0.716) for TRM by 100 days, suggesting better outcomes in P2. This retrospective analysis at a single site indicated that PI-PC treated with amotosalen /UVA stored up to 7 days did not have a negative impact on TRM and OS in HCT recipients, and was an integral part of improving clinical outcomes at our institution. . Table. Disclosures Heim: Novartis: Research Funding. Irsch:Cerus Corporation: Employment, Equity Ownership. Lin:Cerus Corporation: Employment, Equity Ownership. Benjamin:Cerus Corporation: Employment, Equity Ownership. Corash:Cerus Corporation: Employment, Equity Ownership.

Results of Autologous and Allogeneic Transplantation in Patients with Primary Plasma Cell Leukemia: A Large Retrospective Analysis of the Chronic Malignancies Working Party of the EBMT

IntroductionPrimary Plasma Cell Leukaemia (pPCL) is a rare disorder and considered the most aggressive plasma cell dyscrasia. Autologous stem cell transplantation (auto) has been shown to improve outcomes, however the role of allogeneic transplantation (allo) is uncertain. The CIBMTR compared outcomes of 147 patients undergoing auto and allo transplant and demonstrated that while allo patients had significantly lower relapse rates their non-relapse mortality was significantly higher. Further evidence is needed to guide clinicians in choosing between auto versus allo in transplant eligible patients.This study examines the largest cohort of patients with pPCL undergoing auto and allo transplantation.Materials and MethodsA retrospective analysis was undertaken of the European Group for Bone Marrow Transplantation (EBMT) experience of patients with pPCL undergoing transplantation between 1998 and 2014. Only patients who had achieved Complete Response (CR), Partial Response (PR) or Stable Disease (SD) prior to transplantation were included.The primary end point was Overall Survival (OS). We further analysed Progression-Free Survival (PFS), Cumulative Incidence of Relapse (CIR) and Non-Relapse Mortality (NRM).As this is a retrospective study single- and tandem- transplant groups were compared by landmark analysis (4 months post first auto) and dynamic prediction to avoid time bias. We defined tandem transplants (auto-auto or auto-allo) given within 9 months in absence of progression. Dynamic prediction was used to predict long-term outcomes in all patients according to the treatment actually received and without loss of information as in the traditional landmark analysis.ResultsA total of 751 patients were included in the analysis. 70 patients received an allo as first transplant. 681 patients received an auto as first transplant; 239 of these patients went on to receive an elective tandem transplant. 122 had a tandem allo and 117 had a tandem auto.Patients having first allo were younger (median age 47.2 years versus 57.7 years for first auto), had a longer time from diagnosis to transplant (first allo 84.3% transplanted in <12 months versus 93.5% in first auto) and had higher proportion of patients both in CR and SD (CR allo 37.1% versus 32.5% first auto, SD 15.7% allo versus 4.8% in first auto). For patients receiving a tandem allo there was a higher proportion of matched unrelated donor transplants (50% versus 28.6% in first allo) and reduced intensity conditioning (80.3% versus 27.1% in first allo).The median OS was 17.5 months for first allo versus 33.5 months for first auto, while median PFS was 11.7 months for first allo and 14.3 months for first auto. As demonstrated by Figure 1 the OS and PFS curves do cross, therefore LogRank test was not appropriate. At 36 months NRM was 27% for allo versus 7.3% for first auto (p<0.0001) which likely accounts for the differences in OS.Figure 1. OS, PFS, CIR and NRMLandmark analysis at 4 months resulted in a reduction in the number of second transplants analysed to 160 patients. The landmark analysis revealed that there is no significant difference in OS or PFS between the transplant groups, and lower CIR (p=0.07) and only a limited early increase of NRM (p=0.24) in the auto-allo group. These results were substantially confirmed when adjusting for covariates, however the landmark analysis is limited by reduced sample size and non-constant relative risks.Dynamic prediction was made with a horizon time of 3 years for OS and 1 year for PFS. Age and disease status at transplant were included and all transplant strategies were compared to single auto as baseline. This revealed that tandem auto allo had a significant improvement in 1 year PFS with a 44% reduction in risk compared to single auto (HR 0.56, p=0.003). The 3 year predicted OS reveals a trend towards superiority for tandem auto allo versus single auto but it did not reach significance (HR 0.78, p=0.20).ConclusionThis is largest retrospective study examining transplantation in pPCL.Direct comparison of first allo versus first auto shows that in the short term allo upfront has worse outcome, largely due to significant NRM. Landmark analysis and especially dynamic prediction models reveal for the first time that auto-allo has an acceptable NRM and could be preferred to single auto due to lower relapse rates translating into a better PFS and even a trend for OS in the long term. [Display omitted] DisclosuresLawless:Celegene: Honoraria, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. Foà:AMGEN: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; NOVARTIS: Speakers Bureau. Garderet:Takeda: Consultancy; Amgen: Consultancy; Celgene: Consultancy.

Antimicrobial Resistance in Gram-Negative Rods Causing Bacteremia in Hematopoietic Stem Cell Transplant Recipients: Intercontinental Prospective Study of the Infectious Diseases Working Party of the European Bone Marrow Transplantation Group.

This intercontinental study aimed to study gram-negative rod (GNR) resistance in hematopoietic stem cell transplantation (HSCT). GNR bacteremias occurring during 6 months post-HSCT (February 2014-May 2015) were prospectively collected, and analyzed for rates and risk factors for resistance to fluoroquinolones, noncarbapenem anti-Pseudomonas β-lactams (noncarbapenems), carbapenems, and multidrug resistance. Sixty-five HSCT centers from 25 countries in Europe, Australia, and Asia reported data on 655 GNR episodes and 704 pathogens in 591 patients (Enterobacteriaceae, 73%; nonfermentative rods, 24%; and 3% others). Half of GNRs were fluoroquinolone and noncarbapenem resistant; 18.5% carbapenem resistant; 35.2% multidrug resistant. The total resistance rates were higher in allogeneic HSCT (allo-HSCT) vs autologous HSCT (auto-HSCT) patients (P < .001) but similar in community-acquired infections. Noncarbapenem resistance and multidrug resistance were higher in auto-HSCT patients in centers providing vs not providing fluoroquinolone prophylaxis (P < .01). Resistance rates were higher in southeast vs northwest Europe and similar in children and adults, excluding higher fluoroquinolone- and β-lactam/β-lactamase inhibitor resistance rates in allo-HSCT adults. Non-Klebsiella Enterobacteriaceae were rarely carbapenem resistant. Multivariable analysis revealed resistance risk factors in allo-HSCT patients: fluoroquinolone resistance: adult, prolonged neutropenia, breakthrough on fluoroquinolones; noncarbapenem resistance: hospital-acquired infection, breakthrough on noncarbapenems or other antibiotics (excluding fluoroquinolones, noncarbapenems, carbapenems), donor type; carbapenem resistance: breakthrough on carbapenem, longer hospitalization, intensive care unit, previous other antibiotic therapy; multidrug resistance: longer hospitalization, breakthrough on β-lactam/β-lactamase inhibitors, and carbapenems. Inappropriate empiric therapy and mortality were significantly more common in infections caused by resistant bacteria. Our data question the recommendation for fluoroquinolone prophylaxis and call for reassessment of local empiric antibiotic protocols. Knowledge of pathogen-specific resistance enables early appropriate empiric therapy. Monitoring of resistance is crucial. NCT02257931.

Outcome of BONE Marrow Transplantation in Congenital Diskeratosis: Preliminary DATA from the European Group for BONE Marrow Transplantation (EBMT)

▪Hematopoietic Stem cell Transplantation (HSCT) is the definitive treatment for bone marrow failure in diskeratosis congenita (DC). Organ dysfunction (mainly lung and gastrointestinal tract) are often part of the disease and may be a limiting factor for or may affect the final outcome of HSCT. Scarce data or relatively small cohort studies are available in current literature on outcome of HSCT in this disease. We analyzed the outcome of 87 patients diagnosed with DC reported in the data base of the European Society for Blood an Bone Marrow Transplantation (EBMT) who underwent HSCT from 1979 to 2014. In particular we analyzed data on type of HSCT, characteristic of donors, source of cells, incidence of acute and chronic GvHD. Males were 76%. Median age at diagnosis of DC was 5.7 years (0-33 yrs), median age at HSCT was 11.2 years (range 0.56-41 yrs). Median time from diagnosis to HSCT was 19 months (0.62-304 mo). The cell source was bone marrow (BM) in 67%, peripheral blood (PB) in 22% and cord blood (CB) 11%. Twenty six percent of patients were engrafted from a matched related and 53% from a matched unrelated donor. Twenty one percent of subjects were engrafted from a mismatched (both related and unrelated) HSCT. Engraftment was documented in 95% of subjects: 4 % had primary graft failure and 10% lost the graft. Overall 35 patients (40%) died, and 52 were alive (60%) at last follow-up. Causes of death were: infections (43%), multi-organ failure (26%), rejection/oss of graft (14%), GvDH (8.5%) undefined (8.5%). In 32% of cases death was related to transplant. Lung injury was present in 17% of subjects who died. Acute GVDH (mainly grade 2-4) and chronic GvHD occurred in 39% and 30% of cases. Five year OS was 60 %. OS was not significantly different by calendar period (before and after year 2000: 50% vs 67% respectively, p=0.424), by age at transplant (below and above age of 12 years: 64% vs 55% respectively ; p= 0.564) and by source of cells (marrow 60%, cord blood 68%, and peripheral cells 46%; p= 0.687). Conversely, OS in HSCT from mismatched donor was inferior to that of transplants from matched donor (38% vs 65% respectively; p= 0.045). The use of radiotherapy or busulfan (any dose) in the conditioning vs other regimens did not impact on 5 y-OS ( 58% vs 62% respectively; p=0.898). HSCT from HLA matched donor can be considered a treatment option in DC. Transplant related mortality looks rater high. Multi organ failure and lung injury are amongst the main causes of death thus pointing to pre-transplant organ status as important determinant of HSCT outcome. DisclosuresDufour:Pfizer: Consultancy.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Andrea BacigalupoAndrea BacigalupoDr Bacigalupo is the Head of the Division of Hematology and Stem Cell Transplants at Ospedale San Martino, Genova, Italy. He graduated in 1973 from the Genova Medical School, Italy, and started an allogeneic transplant program in 1976. He has conducted several clinical trials in patients with aplastic anemia and in patients undergoing allogeneic transplants. His main interests are bone marrow failure, Graft-versus-Host-Disease (GvHD) and related complications, and graft versus leukemia reactions. He has also been interested in cytomegalovirus and Epstein–Barr virus infections, looking at early diagnosis and prospective studies on prophylaxis and pre-emptive therapy. Dr Bacigalupo has served as a board member of the European Group for Bone Marrow Transplantation (EBMT) for several years, as secretary, then Chairperson of the Aplastic Anemia Working Party and then as President from 1998 to 2002. He served as President of the Italian Group of Bone Marrow Transplantation (GITMO) from 2002 to 2005. He has been a member of the Italian National Health Council for two terms (2000–2006). He has served on the Regimen Related Toxicity Working Group of the Center for International Blood and Marrow Transplant Research (CIBMTR). Dr Bacigalupo has published over 500 articles in peer-reviewed journals and he is a member of several national and international hematology societies. He is Associate Editor of the journal Bone Marrow Transplantation and Biology of Blood and Marrow Transplantation. He serves on the Board of Haematologica and of the Journal of Clinical Oncology. Jed B. GorlinJed B. GorlinDr Jed B. Gorlin is board certified in pediatrics and blood banking and transfusion medicine. Dr Gorlin is the Vice President of Medical and Quality Affairs for Innovative Blood Resources, USA. He received his undergraduate degree from Stanford University, USA, a MD degree from Yale University, USA, and a MBA from the University of Minnesota's Carlson School of Business, USA. Dr Gorlin trained in pediatrics and pediatric hematology/oncology at Boston Children's hospital, USA, and completed research fellowships at Dana-Farber Cancer Institute, USA, Massachusetts General Hospital, USA, Brigham & Women's Hospital, USA, and the Puget Sound Blood Center, USA. Dr Gorlin served on the boards of AABB and the National Blood Foundation. He is currently the Co-Director of Transfusion Medicine at Hennepin County Medical Center, a level one trauma hospital in Minneapolis, USA, and the Children's Hospitals and Clinics in Minneapolis and St. Paul, USA. He is a consultant to AABB and CDC for projects in Rwanda, Tanzania and Central Asia including Kazakhstan and Kyrgyzstan.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Andrea BacigalupoAndrea BacigalupoDr Bacigalupo is the Head of the Division of Hematology and Stem Cell Transplants at Ospedale San Martino, Genova, Italy. He graduated in 1973 from the Genova Medical School, Italy, and started an allogeneic transplant program in 1976. He has conducted several clinical trials in patients with aplastic anemia and in patients undergoing allogeneic transplants. His main interests are bone marrow failure, Graft-versus-Host-Disease (GvHD) and related complications, and graft versus leukemia reactions. He has also been interested in cytomegalovirus and Epstein–Barr virus infections, looking at early diagnosis and prospective studies on prophylaxis and pre-emptive therapy. Dr Bacigalupo has served as a board member of the European Group for Bone Marrow Transplantation (EBMT) for several years, as secretary, then Chairperson of the Aplastic Anemia Working Party and then as President from 1998 to 2002. He served as President of the Italian Group of Bone Marrow Transplantation (GITMO) from 2002 to 2005. He has been a member of the Italian National Health Council for two terms (2000–2006). He has served on the Regimen Related Toxicity Working Group of the Center for International Blood and Marrow Transplant Research (CIBMTR). Dr Bacigalupo has published over 500 articles in peer-reviewed journals and he is a member of several national and international hematology societies. He is Associate Editor of the journal Bone Marrow Transplantation and Biology of Blood and Marrow Transplantation. He serves on the Board of Haematologica and of the Journal of Clinical Oncology. Jed B. GorlinJed B. GorlinA leading authority in transfusion medicine, Dr Jed Gorlin oversees Quality and Regulatory Affairs, Training and Education, and Physician Services at Memorial Blood Centers/Innovative Blood Resources, USA. He provides medical education and transfusion support to hospital partners, and carries the organization's mission and expertise to national and international blood centers, as well as prospective hospital and laboratory clients. He has served on the boards of the AABB and National Blood Foundation, is Director of Transfusion Medicine at Hennepin County Medical Center, USA, and consults with the Minnesota Department of Health. Dr Gorlin has been a consultant to AABB-PEPFAR (President's Emergency Plan for AIDS Relief) projects in Rwanda and Tanzania. He has presented on transfusion preparedness and infectious disease screening at many blood centers in China. He has provided technical assistance for transfusion medicine projects in Kabul, Afghanistan, Kazakhstan and Kyrgyzstan. He is a technical consultant for transfusion response to obstetric hemorrhage to several groups working to reduce the frequency of maternal mortality including, the California Maternal Quality Care Collaborative, the American Congress of Obstetricians and Gynecologists and the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN). The AWHONN has a project funded by Merck for mothers, which has pilot projects to reduce maternal mortality from hemorrhage in New Jersey, Georgia and Washington, DC. Prior to joining Memorial Blood Centers in 1997, Dr Gorlin was acting medical director for transfusion services at Children's Hospital in Boston, USA, and for nearly 10 years held various positions at Children's Hospital and the Dana-Farber Cancer Institute, USA, a principal teaching affiliate of Harvard Medical School, USA. Board certified in pediatrics, and blood banking and transfusion medicine, he received his undergraduate degree from Stanford University, USA, a doctor of medicine degree from Yale University, USA, and a M.B.A. from the University of Minnesota's Carlson School of Business, USA.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Andrea BacigalupoAndrea BacigalupoDr Bacigalupo is the Head of the Division of Hematology and Stem Cell Transplants at Ospedale San Martino, Genova, Italy. He graduated in 1973 from the Genova Medical School, Italy, and started an allogeneic transplant program in 1976. He has conducted several clinical trials in patients with aplastic anemia and in patients undergoing allogeneic transplants. His main interests are immune control of hematopoiesis, bone marrow failure, GvHD and related complications, and graft versus leukemia reactions. He has also been interested in cytomegalovirus and Epstein–Barr virus infections, looking at early diagnosis and prospective studies on prophylaxis and pre-emptive therapy. Dr Bacigalupo has served as a board member of the European Group for Bone Marrow Transplantation (EBMT) for several years, as EBMT Secretary, Chairperson of the Aplastic Anemia Working Party and then as President for the 1998 to 2002 term. He served as President of the Italian Group of Bone Marrow Transplantation (GITMO) for the 2002 to 2005 term. He has been a member of the Italian National Health Council for two terms (2000–2006). He has served on the Regimen Related Toxicity Working Group of the Center for International Blood and Marrow Transplant Research (CIBMTR). He is a member of several national and international hematology societies and is Associate Editor of the journal Bone Marrow Transplantation and Biology of Blood and Marrow Transplantation. He serves on the Board of Haematologica and of the Journal of Clinical Oncology. Dr Bacigalupo has published over 400 articles in peer-reviewed journals. Martin L. OlssonMartin L. OlssonDr Olsson is a Professor of Transfusion Medicine at Lund University, Sweden, and the Medical Director of the Nordic Reference Laboratory for Genomic Blood Group Typing in Lund, Sweden. He received his M.D. and Ph.D. at Lund University and has been a guest scientist at the Bristol Institute of Transfusion Science, UK, and a visiting Associate Professor/Lecturer at Harvard Medical School, Boston, MA, USA. His main clinical and research interests are in the molecular genetics of red cell surface markers with a special emphasis on carbohydrate histo-blood group systems and blood typing. His scientific contributions have focused on clarifying the correlation between red cell phenotypes and the underlying genetic polymorphisms, as well as glycosyltransferase function in different blood groups. He is also interested in pathogen-related aspects of blood group antigens and different mechanisms of protection against hemolysis. Dr Olsson serves as Associate Editor of Transfusion Medicine and is a member of the Editorial Board of Transfusion. His awards include the Jean Julliard Prize from the International Society of Blood Transfusion, the Race and Sanger Award from the British Blood Transfusion Society, the Fernström Prize at Lund University, the Hain Foundation Prize and the Claes F. Högman's Honorary Lectureship.

Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Outcomes in pts refractory to lenalidomide (LEN) and/or bortezomib (BORT).

8016 Background: Response and survival outcomesare poor in pts with RRMM who are refractory to BORT and immunomodulatory drugs. POM+LoDEX has demonstrated activity in pts with advanced multiple myeloma who have received multiple lines of therapy. This analysis evaluates outcomes in pts with disease refractory to LEN, BORT, or both, as well in pts with disease refractory to both LEN and BORT who had received prior transplant. Methods: In the MM-002 phase II trial, pts received POM (4 mg/day on days 1–21 of each 28-day cycle) alone (n=108) or in combination with LoDEX (40 mg/week) (n=113). Refractory disease was defined as documented progression during treatment or within 60 days of the last dose of treatment. Response rates were assessed using European Group for Bone Marrow Transplantation (EBMT) criteria by independent adjudication committee. Results: Patients who received POM+LoDEX were refractory to LEN (77%), BORT (73%), or both (61%). Forty-two percent were refractory to both LEN and BORT and had received prior transplant. Overall, 20% of pts achieved ≥ PR, median PFS was 3.5 months, and 1-year survival rate was 59%. Response rates and duration were comparable in pts with disease refractory to LEN, BORT, or both, and in pts who had received prior transplant (response rate 25-34%, median duration of response 5.7-7 months). Survival outcomes were similar across the groups (median PFS 3.8-4.6 months; 1-year survival rate 60-67%). Conclusions: POM, given at 4 mg/day on days 1–21 of each 28-day cycle in combination with LoDEX, 40 mg/week, is effective in pts with RRMM refractory to LEN, BORT, or both, and including those with prior transplant. These results suggest a lack of cross-resistance between POM and LEN, and confirm activity not only in BORT-refractory pts but also those for whom transplant has failed. [Table: see text]

Successes and Failures of Stem Cell Transplantation in Autoimmune Diseases

Over the past 15 years, more than 1500 patients have received HSCT, mostly autologous, as treatment for a severe autoimmune disease (AD). More than 1000 of these have been registered in the European Group for Bone Marrow Transplantation (EBMT) and European League Against Rheumatism (EULAR) combined database. A recent retrospective analysis of 900 patients showed that the majority had multiple sclerosis (MS; n = 345) followed by systemic sclerosis (SSc; n = 175), systemic lupus erythematosus (SLE; n = 85), rheumatoid arthritis (RA; n = 89), juvenile idiopathic arthritis (JIA; n = 65), and idiopathic cytopenic purpura (ITP; n = 37). An overall 85% 5-year survival and 43% progression-free survival was seen, with 100-day transplantation-related mortality (TRM) ranging between 1% (RA) and 11% (SLE and JIA). Approximately 30% of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many patients, such as in those with SSc, morphological improvement such as reduction of skin collagen and normalization of microvasculature was documented beyond any predicted known effects of intense immunosuppression alone. The high TRM was in part related to conditioning intensity, comorbidity, and age, but until the results of the 3 prospective randomized trials are known, an evidence-based modification of the conditioning regimen will not be possible.(1) In recent years, multipotent mesenchymal stromal cells (MSCs) have been tested in various AD, exploiting their immune-modulating properties and apparent low acute toxicity. Despite encouraging small phase 1/2 studies, no positive data from randomized, prospective studies are as yet available in the peer-reviewed literature.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. Section Editors Andrea BacigalupoAndrea BacigalupoDr Bacigalupo is the Head of the Division of Hematology and Stem Cell Transplants at Ospedale San Martino, Genova, Italy. He graduated in 1973 from the Genova Medical School, and started an allogeneic transplant program in 1976. He has conducted several clinical trials in patients with aplastic anemia and in patients undergoing allogeneic transplants. His main interests are immune control of hematopoiesis, bone marrow failure, GvHD and related complications, and graft versus leukemia reactions. He has also been interested in cytomegalovirus and Epstein–Barr virus infections, looking at early diagnosis and prospective studies on prophylaxis and pre-emptive therapy. Dr Bacigalupo has served as a board member of the European Group for Bone Marrow Transplantation (EBMT) for several years, as EBMT Secretary, Chairperson of the Aplastic Anemia Working Party and then as President for the 1998–2002 term. He served as President of the Italian Group of Bone Marrow Transplantation (GITMO) for the 2002–2005 term. He has been a member of the Italian National Health Council for two terms (2000–2006). He has served on the Regimen Related Toxicity Working Group of the Center for International Blood and Marrow Transplant Research (CIBMTR). He is a member of several national and international hematology societies and is Associate Editor of the journal Bone Marrow Transplantation and Biology of Blood and Marrow Transplantation. He serves on the Board of Haematologica and of the Journal of Clinical Oncology. Dr Bacigalupo has published over 400 articles in peer-reviewed journals. Martin L. OlssonMartin L. OlssonDr Olsson is a Professor of Transfusion Medicine at Lund University, Lund, Sweden and has been a guest scientist at the Bristol Institute of Transfusion Science and a visiting Associate Professor/Lecturer at Harvard Medical School, Boston, MA, USA. He received his medical degree and Ph.D. at Lund University. His main clinical and research interests are in the molecular genetics of red cell surface markers with a special emphasis on carbohydrate histo-blood group systems and blood typing. His scientific contributions have focused on clarifying the correlation between red cell phenotypes and the underlying genetic polymorphisms, as well as glycosyltransferase function in different blood groups. He is also interested in pathogen-related aspects of blood group antigens and different mechanisms of protection against hemolysis, including exoglycosidase-treated red cells for ABO-universal transfusion. Dr Olsson serves as Associate Editor of Transfusion Medicine and is a member of the Editorial Board of Transfusion. His awards include the Jean Julliard Prize from the International Society of Blood Transfusion, the Race and Sanger Award from the British Blood Transfusion Society, the Fernström Prize at Lund University and the Hain Foundation Prize.

Stammzelltherapie bei Autoimmunerkrankungen

Over 1,500 patients world wide have received a hematopoietic stem cell transplant (HSCT) as treatment for a severe autoimmune disease. Most of these have been autologous and mostly have occurred in the past 15 years. Over 1,000 of these have been registered in the European Group for Bone Marrow Transplantation (EBMT) and European League Against Rheumatism (EULAR) combined data base. A recent retrospective analysis of 900 patients (1) showed that the majority had multiple sclerosis (n = 345) followed by systemic sclerosis (n = 175), systemic lupus erythematosus (n = 85), rheumatoid arthritis (n = 89), juvenile idiopathic arthritis (n = 65) and idiopathic cytopenic purpura (n = 37). An overall 85 % 5-year-survival and 43 % progression-free survival was seen, with 100-day-transplant-related-mortality (TRM) ranging between 1 % (rheumatoid arthritis) and 11 % (systemic lupus erythematosus and juvenile idiopathic arthritis). Around 30 % of patients in all disease subgroups had a complete response, often durable despite full immune reconstitution. In many, e. g. systemic sclerosis, morphological improvement such as reduction of skin collagen and normalisation of microvasculature was documented, beyond any predicted known effects of intense immunosuppression alone. The high TRM was in part related to conditioning intensity, comorbidity and age, and the final risk/benefit assessment will be made after the results of the three randomised propective clinical trials are known. [nl]Recently, multipotent mesenchymal stromal cells have been tested in various autoimmune diseases, exploiting their immune modulating properties and apparent low acute toxicity. Despite encouraging small phase I/II studies, no positive data from randomised, prospective studies are as yet available in the peer reviewed literature.

Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study

AbstractAbstract 3023 Background:Elotuzumab is a humanized monoclonal IgG1 antibody directed against a cell surface glycoprotein, CS1, which is highly and uniformly expressed in multiple myeloma (MM). Elotuzumab induces dose-dependent antibody-dependent cellular cytotoxicity (ADCC) against MM cell lines. In vitro pretreatment with bortezomib enhanced elotuzumab-mediated autologous ADCC, and in a murine xenograft model of MM the combination of elotuzumab and bortezomib exhibited synergistic antimyeloma activity. We present updated results of a phase 1 study that evaluated the maximum tolerated dose (MTD) of elotuzumab and the overall safety and clinical responses of the combination of elotuzumab and bortezomib in patients with relapsed/refractory MM. Methods:The study enrolled patients with MM and measurable serum and/or urinary M protein who had received 1 to 3 prior therapies. A 3+3 dose escalation design evaluated 4 escalating doses of elotuzumab (2.5, 5, 10, and 20 mg/kg IV) administered on days 1 and 11 in combination with bortezomib (1.3 mg/m2 IV) administered on days 1, 4, 8, and 11 of a 21-day cycle. Dexamethasone 20 mg PO was added for patients with disease progression after cycle 2 or 3 on days 1, 2, 4, 5, 8, 9, 11, and 12 of subsequent cycles. Patients with stable disease or better after 4 cycles continued treatment until disease progression or unexpected toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1, and responses were assessed during each cycle using European Group for Bone Marrow Transplantation (EBMT) criteria. Results:The 28 enrolled patients had a median time since MM diagnosis of 3.5 years and had received a median of 2 prior therapies; 11 patients (39%) had received prior bortezomib, 4 (14%) were refractory to bortezomib, and 12 (43%) were refractory to their last therapy. Three patients each received the 2.5, 5, and 10 mg/kg doses of elotuzumab and 19 received 20 mg/kg. No DLTs were observed during cycle 1 and the MTD was not reached. After a median of 6 cycles of therapy (range, 1–25 cycles), 2 patients remain on therapy. Serious adverse events related to elotuzumab were 1 grade 3 chest pain and 1 grade 3 gastroenteritis. The most frequent grade 3/4 AEs were lymphopenia (25%), fatigue (14%), thrombocytopenia, neutropenia, hyperglycemia, peripheral neuropathy, and pneumonia (11%), and leukopenia and anemia (7%). Twenty-seven patients completed at least 2 cycles of therapy or progressed earlier and were therefore evaluable for response (Table). An objective response (≥ PR) was observed in 13/27 (48%) evaluable patients, including 7% CR and 41% PR. A clinical response (≥ MR) was seen in 17/27 (63%) evaluable patients. Notably, a partial response was seen in 2 (50%) of 4 patients refractory to prior bortezomib. The objective response rate (ORR) was 60% (6/10), 50% (6/12), and 20% (1/5) in patients who had received 1, 2, or 3 previous lines of therapy, respectively. Analysis of bone marrow plasma cells indicated that 10 and 20 mg/kg elotuzumab doses resulted in complete or near complete saturation of CS1 sites by elotuzumab. Median time to progression was 9.46 months in the overall population as well as in the bortezomib-naïve population. Conclusions:The combination of elotuzumab and bortezomib had a manageable safety profile. Key toxicities attributable to elotuzumab appeared to be related to infusion reactions. The combination showed promising efficacy with an ORR of 48% and a clinical response rate of 63%. Notably, activity was seen in bortezomib-refractory patients (ORR = 50%). The median time to progression was 9.46 months for both the overall and the bortezomib-naïve populations. Disclosures:Jakubowiak:Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson, Centocor Ortho Biotech: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor Ortho Biotech: Speakers Bureau. Off Label Use: Elotuzumab In Combination with Bortezomib In Patients with Relapsed/Refractory Multiple Myeloma: Updated Results of a Phase 1 Study. Bensinger:Millennium Pharmaceuticals, Celgene Corp., Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siegel:Celgene and Millennium: Advisory Board, Speakers Bureau; Merck: Advisory Board. Zimmerman:Millennium, Celgene: Speakers Bureau. Mohrbacher:Millennium: Speakers Bureau. Richardson:Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Afar:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Anderson:Millennium, Celgene, Novartis, Onyx, Merck, Bristol-Myers Squibb: Consultancy; Acetylon: Stock Options; Acetylon: Membership on an entity's Board of Directors or advisory committees.

Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation in Metastatic Colorectal Cancer as a Novel Adoptive Cell Therapy Approach. The European Group for Blood and Marrow Transplantation Experience

Reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (HCT) allowed the existence of an allogeneic cell-mediated antitumor effect in metastatic colorectal cancer (mCRC) to be explored. We report on 39 patients with progressing mCRC treated with different RIC regimens in a multicenter clinical trial of the European Bone Marrow Transplantation Group. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (15%), and partial response (PR) in 2 (5%). All patients engrafted (median donor T cell chimerism of 90% at day +60). Transplant-related morbidities were limited. Grades II-IV acute graft-versus-host disease (aGVHD) occurred in 14 patients (35%) and chronic GVHD (cGVHD) in 9 patients (23%). Transplant-related mortality occurred in 4 patients (10%). The best tumor responses were: 1 complete response (CR) (2%), 7 PR (18 %), and 10 SD (26%), giving an overall disease control in 18 of 39 patients (46%). Allogeneic HCT after RIC is feasible; the collected results compared favorably in terms of tumor response with those observed using conventional approaches beyond second-line therapies. The study of an allogeneic cell based therapy in less advanced patient s is warranted.

High-dose chemotherapy with peripheral blood progenitor cell support for patients with non-small cell lung cancer: the experience of the European Group for Bone Marrow Transplantation (EBMT) Solid Tumours Working Party

We report the experience of the EBMT Solid Tumours Working Party (STWP) using high-dose chemotherapy (HDCT) with PBPC support in patients with non-small cell lung cancer (NSCLC). Between 1989 and 2004, 36 NSCLC patients (27 men and 9 women), median age 53.5 years (range: 24-62) were treated with 63 HDCT courses. A high-dose carboplatin-based regimen was used in 53% of the cases. Thirty-two patients had relapsed/metastatic disease, while four classified as stage IIIB received HDCT followed by radiotherapy. No treatment-related death occurred. Of 25 patients who were planned to receive multi-cycle HDCT, 4 cases (16%) interrupted the treatment early due to prolonged severe toxicities and 4 (16%) due to progressive disease. Of 36 evaluable patients, 3 (8%) achieved a complete remission and 13 (36%) had a partial remission at an overall response rate of 44%. Of these, one patient with stage IIIB and one with stage IV are alive disease free at 71+ and 149+ months, respectively. After a median follow-up of 48 months (range: 6-149), median survival was 7 months (range: 1-149). Despite one anecdotal case, HDCT did not show significant activity, but induced relevant morbidity in NSCLC patients.

Nuclear terrorism: the role of hematology in coping with its health consequences

This review reports on a novel approach to use blood cell change patterns after accidental whole body radiation exposure (to be expected as a consequence of nuclear terrorism) as reliable indicators of effect and as an aid to plan therapeutic measures. There is growing concern about the potential of nuclear terrorism. Several scenarios are being discussed. In all of them one finds elements that mimic the experience gained in assessing and treating humans who were exposed to ionizing radiation in radiation accidents. This experience leads to diagnostic and therapeutic measures laid down in a recently published Manual on the Acute Radiation Syndrome. The European Bone Marrow Transplantation Group (EBMT) together with the Institut de Radioprotection et de Sûreté Nucléaire (IRSN) in Paris and the University of Ulm published a consensus paper to use 'response categories' based on organ-specific gradings of severity as indicators of the severity of health impairments. The implication of this review is obvious: the medical staff confronted suddenly with the challenge of clinically managing an irradiated person will find all scientifically based recommendations in order to cope with the evolving problems on a scientific-pathophysiology driven approach.

Pegfilgrastim compared with Filgrastim after autologous hematopoietic peripheral blood stem cell transplantation

In order to assess the effect of Pegfilgrastim on the duration of neutropenia and clinical outcome of patients after autologous peripheral blood stem cell (PBSC) transplantation, we compared 20 consecutive patients with lymphoma or multiple myeloma receiving a single 6-mg dose of Pegfilgrastim on day 1 posttransplant to an historical control group of 60 patients receiving daily Filgrastim 5 microg/kg starting on day 1 posttransplant. The duration of neutropenia was similar in the Pegfilgrastim group compared with the control group. There were no differences in time to neutrophil, erythroid, or platelet engraftment nor in the incidence of fever and infections. The duration of antibiotic therapy, transfusion support, and time to hospital discharge were similar in the two groups. However, after initial hematopoietic reconstitution, we observed significantly higher values of lymphocytes (e.g., 1,660+/-1,000 versus 970+/-460 on day 80, p=0.0002), neutrophils (e.g., 3,880+/-2,030 versus 2,420+/-1,500 on day 25, p=0.0004), reticulocytes (e.g., 148,160+/-90,590 versus 87,140+/-65,920 on day 25, p<0.0001), and platelets (e.g., 210,700+/-116,090 versus 150,240+/-58,230 on day 55, p=0.0052) up to day 100 in the Pegfilgrastim group compared with the Filgrastim group. These observations had no impact on clinical outcome of the patients after day 30 due to the low incidence of infectious events after engraftment in autologous PBSC transplantation. We conclude that the effect of Pegfilgrastim administrated on day 1 posttransplant is comparable to that of daily Filgrastim on initial hematopoietic reconstitution. The possibly superior effect of Pegfilgrastim on cell counts we observed after initial engraftment should be further tested in a prospective randomized trial.

Reduced intensity regimen using low dose total body irradiation prior to allogeneic transplant for hematologic malignancies: A retrospective review from the acute leukemia working party of the European Bone Marrow Transplant Group

6675 Background: One the main limitations myeloablative regimens is its high toxicity. This has led to the development of non-myeloablative procedures which allow for initial engraftment of stem cells and subsequent transfer of immune cells for the induction of graft-versus-tumor reaction. In this setting the impact of the low dose TBI parameters on outcome have never been studied. Methods: Data of 106 patients (pts) treated between 1998 and 2003 were analyzed. Median age was 50y (3–72), male to female ratio: 65/41. Hematologic malignancies included AML (n=26), other leukemias (n=30), myeloproliferative syndrome or myelodysplasia (n=12), lymphoma (n=23) and myeloma (n=15). Allogeneic transplant were performed from HLA identical sibling donor (n=79), MUD (n=23) or unmatched related donors (n=4). TBI delivered 2Gy in 1 fraction in 77pts whereas 29pts received a total dose 4–6Gy. The median dose rate (DR) was 0.105 (0.06–0.57) Gy/min. Results: The median follow-up was 17 (1–62) m. Engraftment was obtained in 99pts. Full chimerism was observed in 44 (61%) pts. GVHD grade I to IV was developed in 13, 19, 13, 11, respectively. it was not influenced by the TBI dose (p=0.31) or DR (p=0.27). In Univariate analyses, the 2-year LFS tends to be higher after TBI > 2Gy and using DR ≥ 0.1 Gy/min. LFS was significantly better for pts in complete remission (52% vs 34%; p=0.006), for female donor to male recipient (52% vs 36%; p=0.04), HLA id sibling donor (52% vs 12%; p<0.0001). Multivariate analysis showed 2 independent factors for relapse and LFS: HLA id sibling donor (p=0.0002; RR:12 and p<0.0001; RR: 0.18) and CR (p=0.0009; RR: 0.06 and p=0.0006; RR: 3.46). For overall survival the 3 independent factors were: CR (p=0.001, RR:3.3), HLA id sibling donor (p=0.0003; RR=0.19) and DR (p=0.02; RR:2.07). Conclusion: In this multicenter retrospective study we found that remission status and HLA sibling donor influence independently the outcome. DR seems to have an impact on OS. Incidence of GVHD, engraftment and chimerism are similar to the literature. No significant financial relationships to disclose.