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Hodgkin lymphoma (HL) patients who relapse after autologous-stem-cell- transplantation (auto-SCT) have traditionally had a poor prognosis. We analyzed 1781 adult HL patients who relapsed between 2006 and 2017 after a first auto-SCT. The 4-year overall survival (OS) after relapse continuously increased from 32% for patients relapsing in 2006-2008, to 63% for patients relapsing in 2015-2017 (p = 0.001). The improvement over time was predominantly noted in patients who had an early relapse (within 12 months) after auto-SCT (p = 0.01). On multivariate analysis, patients who relapsed in more recent years and those with a longer interval from transplant to relapse had a better OS, whereas increasing age, poor performance status, bulky disease, extranodal disease and presence of B symptoms at relapse were associated with a worse OS. Brentuximab vedotin (BV), checkpoint inhibitors (CPI) and second transplant (SCT2; 86% allogeneic) were used in 233, 91 and 330 patients respectively. The 4-year OS from BV, CPI, and SCT2 use was 55%, 48% and 55% respectively. In conclusion, the outcome after post-transplant relapse has improved significantly in recent years, particularly in the case of early relapse. These large-scale real-world data can serve as benchmark for future studies in this setting.

Aplastic anemia is a relatively rare but potentially fatal disorder, with a reported higher incidence in developing countries in comparison to the West. There are significant variations in epidemiological as well as etiological factors of bone marrow failure syndromes in the developing countries in comparison to the developed world. Furthermore, the management of bone marrow failure syndromes in resource constraint settings has significant challenges including delayed diagnosis and referral, limited accessibility to healthcare facilities, treatment modalities as well as limitations related to patients who require allogeneic stem cell transplantation. Here we will provide a review of the available evidence related to specific issues of aplastic anemia in the developing countries and we summarize suggested recommendations from the Eastern Mediterranean blood and bone marrow transplantation (EMBMT) group and the severe aplastic anemia working party of the European Society of blood and marrow transplantation (SAAWP of EBMT) related to the diagnosis and therapeutic options in countries with restricted resources.

The development of hematopoietic stem cell transplantation (HSCT) programs can face significant challenges in most developing countries because such endeavors must compete with other government health care priorities, including the delivery of basic services. Although this is may be a limiting factor, these countries should prioritize development of the needed expertise to offer state-of-the-art treatments, including transplantation, by providing financial, technological, legal, ethical, and other needed support. This would prove beneficial in providing successful programs customized to the needs of their population and potentially provide long-term cost savings by circumventing the need for their citizens to seek care abroad. The costs of establishing an HSCT program and the costs of the HSCT procedure itself can be substantial barriers in developing countries. In addition, socioeconomic factors intrinsic to specific countries can influence access to HSCT, patient eligibility for HSCT, and timely utilization of HSCT center capabilities. This report describes recommendations from the Worldwide Network for Blood and Marrow Transplantation for establishing HSCT programs, with a specific focus on developing countries, and identifies challenges and opportunities for providing this specialized procedure in resource-constrained settings.

Background: Patients undergoing hematopoietic stem cell transplantation (HSCT) are often referred for physical therapy (PT) to help improve their quality of life. However, to our knowledge there is no clear PT pathway to guide therapists and patients before, during, and after HSCT. Methods: A comprehensive literature review was carried out exploring the role and benefits of PT in HSCT patients. The current evidence was comlimented with recommendations and opinions from the experts in the field, which included PT's and hematology consultants from PTAGVHD and the EMBMT group. Result: A clear pathway and protocol as a working guide for rehabilitation professionals working with the HSCT patient's was developed. Conclusion: This paper not only reviews the current evidence on safe PT practice but also puts forward a protocol and pathway for HSCT rehabilitation, highlights the importance of individualized exercise intervention for HSCT patients, and outlines safe practice guidelines for the physical therapists working in this field. Keywords: Hematopoietic stem cell transplantation, Physical therapy, Rehabilitation

The World Health Organization-designated Eastern Mediterranean region (EMRO) consists of 22 countries in North Africa and Western Asia with a collective population of over 679 million. The area comprises some of the wealthiest countries per capita income and some of the poorest. The population structure is also unique and contrasts with western countries, with a much younger population. The region sits in the heart of the thalassemia belt. Many countries have a significant prevalence of sickle cell disease, and cancer is on the rise in the region. Therefore, the strategic priorities for the growth and development of hematopoietic stem cell transplantation (HSCT) differ from country to country based on resources, healthcare challenges, and prevalent infrastructure. Thirty-one reporting teams to the Eastern Mediterranean Blood and Marrow Transplantation Group have active HSCT programs in 12 countries; allogeneic transplants outnumber autologous transplants, and the proportion of allotransplants for non-malignant conditions is higher in the EMRO region than in Western Europe and North America. The vast majority (99%) of allotransplants are from matched related donors. Matched unrelated donors and other alternate donor transplants are underutilized. The chance of finding a matched related donor for allografts is higher, with a significant chance of finding matched donors among non-sibling related donors. Reasons for relatively lower rates of transplants compared with other countries are multifactorial. Capacity building, development of newer centers, innovative funding, and better utilization of information technology are required to make transplantation as an accessible modality to more patients. Cost-effectiveness and cost-containment, regulation, and ensuring quality will all be priorities in planning HSCT development in the region.

Aplastic anemia is a relatively rare but potentially fatal disorder, with a reported higher incidence in developing countries in comparison to the West. There are significant variations in epidemiological as well as etiological factors of bone marrow failure syndromes in the developing countries in comparison to the developed world. Furthermore, the management of bone marrow failure syndromes in resource constraint settings has significant challenges including delayed diagnosis and referral, limited accessibility to healthcare facilities, treatment modalities as well as limitations related to patients who require allogeneic stem cell transplantation. Here we will provide a review of the available evidence related to specific issues of aplastic anemia in the developing countries and we summarize suggested recommendations from the Eastern Mediterranean blood and bone marrow transplantation (EMBMT) group and the severe aplastic anemia working party of the European Society of blood and marrow transplantation (SAAWP of EBMT) related to the diagnosis and therapeutic options in countries with restricted resources.

Human recombinant granulocyte colony stimulating factor reduces the duration of neutropenia following HLA-identical allogeneic bone marrow transplantation. However, its use remains controversial due to the risk of increasing the incidence of acute graft-versus-host disease (GVHD) and slower platelet recovery. To clarify these risks, we conducted a prospective randomized placebo-controlled trial of filgrastim 5 µg/kg/day i.v. from day 7 post-transplant until neutrophil recovery in 145 consecutive adults undergoing HLA-identical allogeneic bone marrow transplantation, with cyclosporine and methotrexate as GVHD prophylaxis. The primary endpoint was the incidence of acute GVHD; hematological recovery, nonrelapse mortality, and post-transplant complications were secondary endpoints. Filgrastim had no significant effect on the incidence of acute GVHD, platelet recovery, platelet transfusion requirements, chronic GVHD, or survival. Filgrastim accelerated granulocyte recovery significantly (with absolute neutrophil counts >.5 × 109/L achieved after a median of 16 days versus 23 days for placebo; P

Salvage chemotherapy and autologous stem cell transplantation (auto-SCT) results in the cure of around 50% of patients with Hodgkin lymphoma (HL) failing first line therapy. In historical data, patients who progressed after auto-SCT had a poor outcome, with a median overall survival (OS) of around 1-2 years. Significant progress has been achieved in the last decade with the use of brentuximab vedotin (BV) or check-point inhibitors (CPI) and the increasing use of haploidentical transplant. However, little information is available about the characteristics and real-world outcomes of patients with HL relapsing after auto-SCT in the current era. To assess prognosis of patients with recurrent-HL post auto-SCT over time, we analyzed the European Blood and Marrow Transplant registry data of 1781 adult HL patients who relapsed between 2006 and 2017 after a first auto-SCT. A specific questionnaire was sent to all participant centers to obtain additional data regarding characteristics of the patients, treatment of relapse and outcome after auto-SCT failure. Detailed data were collected for 760 patients [median age 32; interquartile range (IQR) 25-42] included in this study. After a median follow-up for alive patients of 57 months (IQR: 29-89), the 4-year OS after relapse for the 760 included patients was 46% (95%CI: 43-50) and similar to that of 1021 non-included patients (45%, 95%CI: 41-48). The 4-year OS after relapse continuously increased from 35% (95%CI: 27-45) for 136 patients relapsing in 2006-2008, to 43% (95%CI: 37-49) for 258 patients relapsing in 2009-2011, 49% (95%CI: 43-56) for 238 patients relapsing in 2012-2014, and 61% (95%CI: 52-72) for 128 patients relapsing in 2015-2017 (p=0.001) (Figure 1). Improvement over time was predominantly noted in patients who had an early relapse (within 12 months) after auto-SCT (p=0.01) but not in those with a late relapse (p=0.6). On multivariate analysis, patients who relapsed in more recent years and those with a longer interval from transplant to relapse had a better OS, whereas increasing age, poor performance status at relapse, bulky disease at relapse, extranodal disease at relapse and presence of B-symptoms at relapse were associated with a worse OS. Regarding treatment at relapse, BV was used in 233 patients (31%) after a median of 2 months from relapse (IQR: 0.8-8), predominantly as first treatment of relapse (155 patients). BV use increased over the 4 time periods from 3% to 19%, 49% and 49% respectively, and resulted in a complete remission (CR) in 46% and a partial response (PR) in 32%. The 4-year OS from BV use for relapse after auto-SCT was 56% (95%CI: 49-64). CPI were used in 91 patients (12%) including nivolumab in 75 patients and pembrolizumab in 12 patients after a median of 18 months from relapse (IQR: 5-35). CPI use increased over the 4 time periods from 1% to 4%, 14% and 35% respectively, and resulted in a CR of 44%, PR 32%, with a 4-year OS from CPI use of 44% (95%CI: 30-63). Finally, a second SCT (SCT2) was performed in 330 patients (43%) predominantly allogeneic SCT (285 patients, 86%) including a haploidentical SCT in 54 patients (16%). SCT2 was performed in 40% and 37% of patients relapsing in 2006-2008 and 2009-2011 respectively but its use increased to 49% and 51% of patients relapsing in 2012-2014 and 2015-2017 respectively. Four-year OS after SCT2 was 55%. In conclusion, outcome after post-transplant relapse has improved significantly in recent years, particularly in the case of early relapse, possibly reflecting, among other factors, the efficacy of post-transplant salvage including BV, CPI and second transplant. These large-scale real-world data can serve as benchmark for future studies in that setting. Figure 1 Disclosures Blaise: Jazz Pharmaceuticals: Honoraria. Sureda Balari:Incyte: Consultancy; Celgene: Consultancy, Honoraria; BMS: Speakers Bureau; Roche: Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria.

Hematopoietic Stem Cell Transplantation (HSCT) is the only potentially curative treatment option for the hematologic complications that occur in patients with Fanconi anemia (FA). In this study, we present a retrospective multicenter analysis from the Eastern Mediterranean Blood and Marrow Transplantation Group (EMBMT) of matched related donor HSCT for FA in adolescents and adults transplanted between 1988 and 2015. Forty-five patients received HSCT with a median age at transplant of 18 years, the interquartile range (IQR) (15–23.5); 25 (55.6%) patients were females and 20 (44.4%) were males. Conditioning regimen was fludarabine-based in 29 (64.4%) patients, irradiation-based in five (11.1%) patients, and the remaining patients received other combinations. Indication for HSCT was bone marrow failure in 39 (86.7%) and myelodysplastic syndrome in six (13.3%) patients. Stem cell source was bone marrow in 22 (48.9%), peripheral blood in 20 (44.4%), umbilical cord blood in one (2.2%), and combination of bone marrow and cord blood in two (4.4%) patients. Twenty-seven (60%) patients engrafted and five (11.1%) had primary engraftment failure. The median time to neutrophil engraftment was 14 days (range 10–21 days); median time for platelet engraftment was 17 days (10–33 days). The probability of developing grade II–IV acute GVHD for all patients was 7.0% and chronic GVHD 36.6%. No new malignancies were reported. The OS probability was 53.6% (95% CI, 38.3–68.9%) with a median follow-up of 13 months (95% CI, 1–240). Our HLA-matched related HSCT results in AYA patients with FA compare favorably with other reported international registry data.

Bronchiolitis obliterans (BO) is a serious lung complication that can develop after allogenic stem cell transplantation. It has been suggested that single nucleotide polymorphisms (SNPs) that affect the NOD2/CARD15 gene impair its function and result in an uncontrolled innate immune response in the recipient, thereby leading to BO. One hundred eighty-one donor-recipient pairs were analyzed for the association between NOD2 gene variants (SNP8 [Arg702Trp], SNP12 [Gly908Arg], and SNP13 [Leu1007fsinsC]) and the occurrence of BO. Ten patients (2.8%) developed this complication. The incidence of BO increases in recipient variant patient group from 4.7% to 23% in donor Wild-type group in SNP8 (p 0.001). The incidence rose to 19% when the recipient carried the SNP12 variant (p 0.001) in the Tunisian population. Analyses demonstrated that recipient NOD2CARD15 variants (SNP8 and SNP12) present a greater risk in developing BO than recipients without mutation. Our study demonstrated that NOD2/CARD15 typing may be useful in identifying patients at high risk for BO.

Objective/Background: The Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) group has accumulated over 31 years of data and experience in hematopoietic stem cell transplantation (HSCT), particularly in hemoglobinopathies, severe aplastic anemia, inherited metabolic and immune disorders, in addition to a wide array of hematologic malignancies unique to this region. A regional update in current HSCT trends is highly warranted. We studied the trends of HSCT activities in World Health Organization-Eastern Mediterranean (EMRO) region, surveyed by the EMBMT, between 2011 and 2012. Methods: Retrospective analysis of the survey data mainly of cumulative number of transplants, types of transplants (autologous vs. allogeneic), types of conditioning such as myeloablative versus reduced intensity was conducted. Also, trends in leukemias, hemoglobinopathies, severe aplastic anemia, inherited bone marrow failure syndromes, amongst others were analyzed. Results: Twenty-one teams from nine EMRO countries reported their data (100% return rate) to the EMBMT for the years 2011–2012, with a total of 3,546 first HSCT (1,670 in 2011; 1,876 in 2012). Allogeneic HSCT (allo-HSCT) represented the majority (62%) in both years. The main indications for allo-HSCT were acute leukemias (988; 46%), bone marrow failure syndromes (421, 20%), hemoglobinopathies (242; 11%), and immune deficiencies (157; 7%). There was a progressive increase in the proportions of chronic myeloid leukemia cases transplanted beyond first chronic phase (37 [7%] of all chronic myeloid leukemia cases in 2011 vs. 39 [29%] in 2012). The main indications for autologous transplants were multiple myeloma/plasma cell disorders (510; 39%), Hodgkin lymphoma (311; 24%), non-Hodgkin lymphoma (259; 20%), and solid tumors (163; 12%). Reduced intensity conditioning continued to show a progressive decrease over years (9.5% in 2011 vs. 7.9% in 2012), yet remained relatively low compared with contemporary practices in Europe published by EBMT. The vast majority (91%) of allo-HSCT source was from sibling donors with continued dominance of peripheral blood (64%) followed by bone marrow (33%).While umbilical cord blood transplants increased to 4% of allo-HSCT, matched unrelated donor remained underutilized and there was no haplo-identical transplant reported. Large centers with >50 HSCT/year, showed a continued increase in the total number of allo-HSCT over the past 2 years that may be related to capacity building issues and require further studies. Conclusion: There is a discernable increase of HSCT rate in the EMRO region with a significant expansion in utilization of cord blood transplants and allogeneic peripheral blood-HSCT as a valuable source. However, further research of outcome data and the development of regional donor banks (cord blood and matched unrelated donors) may help to facilitate future planning to satisfy the escalating regional needs and augment collaboration within the EMBMT and globally. Keywords: Conditioning, EMRO, Hematopoietic stem cell transplantation, Stem cell source

BM failure (BMF) is a major and frequent complication of dyskeratosis congenita (DKC). Allogeneic hematopoietic SCT (allo-HSCT) represents the only curative treatment for BMF associated with this condition. Transplant-related morbidity/mortality is common especially after myeloablative conditioning regimens. Herein, we report nine cases of patients with DKC who received an allo-SCT at five different member centers within the Eastern Mediterranean Blood and Marrow Transplantation Registry. Between October 1992 and February 2011, nine DKC patients (male, 7 and female, 2), with a median age at transplantation of 19.1 (4.9-31.1) years, underwent an allo-HSCT from HLA-matched, morphologically normal-related donors (100%). Preparative regimens varied according to different centers, but was reduced intensity conditioning (RIC) in eight patients. Graft source was unstimulated BM in five cases (56%) and G-CSF-mobilized PBSCs in four (44%) cases. The median stem cell dose was 6.79 (2.06-12.4) × 10(6) cells/kg body weight. GVHD prophylaxis consisted of CsA in all nine cases; MTX or mycophenolate mofetil were added in five (56%) and two (22%) cases, respectively. Anti-thymocyte globulin was administered at various doses and scheduled in four (44%) cases. Median time-to-neutrophil engraftment was 21 (17-27) days. In one case, late graft failure was noted at 10.4 months post allo-HSCT. Only one patient developed grade II acute GVHD (11%). Extensive chronic GVHD was reported in one case, whereas limited chronic GVHD occurred in another four cases. At a median follow-up of 61 (0.8-212) months, seven (78%) patients were still alive and transfusion independent. One patient died of metastatic gastric adenocarcinoma and graft failure was the cause of death in another patient. This study suggests that RIC preparative regimens are successful in inducing hematopoietic cell engraftment in patients with BMF from DKC. Owing to the limited sample size, the use of registry data and heterogeneity of preparative as well as GVHD prophylaxis regimens reported in this series, we are unable to recommend a particular regimen to be considered as the standard for patients with this disease.

Introduction This practice survey is conducted to analyze clinical hematopoietic stem cell transplantation (HSCT) practice variability among centers in the WHO Eastern Mediterranean Region (EMRO), as represented by the Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) group. Method This internet based survey was completed by the medical program directors of the EMBMT centers; 17 centers participated. The survey collected data on various clinical aspects of HSCT practice. Results Consistency in pre HSCT cardiac (100%), pulmonary (82%) and viral screen (100%) was observed. Obtaining informed consent was universal. Pre-HSCT psychological assessment is practiced in 50% of the centers. All centers used single-bedded rooms with HEPA filters. Visitor policy during neutropenic phase and the use of gowns, masks or gloves when examining patients varied among centers. MRSA/VRE screen and use of low bacterial diet were applied in 65% and 82%, respectively. Anti-bacterial prophylaxis is employed in 58% (Auto-SCT) and 60% (Allo-SCT) of the centers. Drug choice varied (cotrimoxazole, ciprofloxacin, levofloxacin, piperacillin–tazobactam); 60% of the centers used penicillin prophylaxis in GVHD patients. PCP prophylaxis is applied in 58% (Auto-SCT) and 87% (Allo-SCT) of the centers; cotrimoxazole is usually used. Anti-viral prophylaxis with acyclovir or, less commonly, valacyclovir is used in 70% (Auto-SCT) and 93% (Allo-SCT) of centers. Anti-fungal prophylaxis is applied in 70% (Auto-SCT), 93% (myeloablative Allo-SCT) and 87% (reduced intensity [RIC] Allo-SCT). Fluconazole is used in all Auto-SCT and majority of Allo-SCT recipients; few centers used other agents (itraconazole, voriconazole, amphotericin B) in Allo-SCT. Prophylactic GCSF use varied among centers: Auto-SCT 77%, myeloablative Allo-SCT 33%, RIC Allo-SCT 27%. Use of ursodeoxycholic acid for venoocclusive disease (VOD) prophylaxis is variable: 60% (Allo-SCT) and 12% (Auto-SCT). Cyclosporine/methotrexate is the most commonly used GVHD prophylaxis in myeloablative Allo-SCT (93%); heterogeneity was seen in RIC SCT. Treatment of steroid refractory acute GVHD varied (ATG 53%, higher steroid dose 40%). CMV monitoring varied between antigenemia (53%) and PCR (40%) techniques. Pre-emptive anti CMV therapy is used in 86% of the centers, while 7% used routine CMV prophylaxis; 7% had no specific CMV management policy. Conclusion Consistency was observed in areas of pre-SCT work up, use of single rooms, HEPA filters and GVHD prophylaxis. Heterogeneity is observed in other practice aspects including other isolation measures, anti-microbial prophylaxis, VOD prophylaxis, growth factor use and treatment of steroid refractory GVHD. Further studies are needed to probe the impact of such practice variations on post-transplant outcome and to ascertain the best clinical practice approach.

We report a case of autoimmune polyglandular syndrome type II that developed in an 11-year-old boy with homozygous sickle cell disease after allogeneic bone marrow transplant; the donor was his father, who was human leukocyte antigen identical and had vitiligo. On day 24 after transplant, the patient developed grade 1 acute graft-versus-host disease, which was controlled over a period of 3 months with corticosteroid-induced immunosuppression. Full donor engraftment was documented on day 31 after transplant, and this was further confirmed on days 59, 231, 321, 472, 549, and 720. Three months after transplant, the recipient developed adrenal insufficiency, and at 13 months, he developed vitiligo. Seventeen months after transplant, autoimmune thyroid disease, positive for thyroid peroxidase and thyroglobulin autoantibodies, was diagnosed. At the same time, we identified adrenal insufficiency in the donor. We analyzed a serum sample from the recipient for autoantibody markers for type 1 autoimmune diabetes mellitus. The sample was positive for antiglutamic acid decarboxylase. Antibody against 21-hydroxylase enzyme was also found (261 U/mL; normal value, < 1 U/mL). We conclude that the recipient developed autoimmune polyglandular syndrome type II after bone marrow transplant from his father, who was probably affected by the same syndrome.

A 27-year-old man with severe aplastic anemia underwent bone marrow transplantation from his HLA identical brother in July 2016. Conditioning included ATGAM 30 mg/kg for 3 days and Cyclophosphamide 50 mg/kg for 4 days. The patient received several platelet and red blood cell transfusions before and after the conditioning. The patient received broad spectrum antibiotics and caspofungin because persistant febrile neutropenia without bacteriological or mycological documentation. Hemophagocytic syndrome was diagnosed on day +12. Steroids at 1 mg/kg were started on day +12. Fever resolved the same day but resumed 3 days later associated to intravascular hemolysis with no schizocytes on blood smears and negative DAT. Thick blood film smears performed on day +26 revealed Plasmodium falciparum parasites (parasitemia = 20%). Except the level of parasitemia, there were no signs of gravity. Quinine was started on day 26 at a loading dose of 15 mg/kg followed by 8 mg/kg three times a day for 20 doses. Fever vanished after 2 days. Parasitemia cleared in 3 days and remained negative thereafter. Investigations revealed that the patient was transfused by a red cell unit harvested in a voluntary donor native of a malaria endemic country. PCR for P. falciparum performed in this donor in the frame of investigations was positive. The patient is alive with a normal blood count 1 year after BMT.

Graft-versus-Host disease (GVHD) has been widely linked to immunogenetic causes such as disparity between the recipient and its HLA geno-identical donor for some Non-HLA antigens called minor histocompatibility antigens (MiHAgs). HA-2 is one of potential human MiHAgs but its effect on the GVHD occurrence remains not clear. In order to examine such association in the Tunisian cohort of HSCs recipients, we performed a retrospective study on patients who received an HLA-identical HSCT between 2000 and 2009. The study was performed on 60 HLA-A2-positive patients who had received a haematopoietic stem cell transplant from an HLA-identical sibling. All patients received cyclosporine A and/or methotrexate for GVHD prophylaxis. HA-2 genotyping assay was performed with SSP-PCR method and HLA-A*0201 positive samples were identified mainly with Luminex HLA-Typing method. Luminex HLA-Typing assay showed that only 53 cases were positives for the HLA-A*0201 allele. Among these cases, only 3 pairs were mismatched for the MiHAg HA-2. Acute GVHD occurred in 01 HA-2-mismatched pair while chronic GVHD was detected in 02 disparate couples. Univariate and multivariate analyses showed that MiHAg HA-2 disparity does not have any significant effect on the occurrence of either acute or chronic GVHD. This last one appeared to be correlated only with the age of patient (adulthood) (p: 0.011, OR: 22.092). Our findings support the previously reported data denying the influence of the HA-2 disparity on the GVHD occurrence after HSCT.

The aim of this prospective observational study was to evaluate the incidence of hemophagocytic syndrome (HPS) after hematopoietic stem cell transplantation (HSCT). Between July 2006 and December 2007, all patients who received a HSCT in our institution were included in this study. All the following criteria were needed for the diagnosis of HPS: sustained fever over 7 days; cytopenia (neutropenia and/or thrombocytopenia); presence of more than 3% mature macrophages in bone marrow; hyperferritinaemia (>1,000 ng/mL). During this study, 171 patients received a HSCT (68 allogeneic and 103 autologous). The median age was 32 years (3-62). We observed six cases of HPS (6/68; 8.8%) after allogeneic stem cell transplantation (ASCT): one case of EBV-related HPS, two cases of CMV-related HPS, and three cases with no evidence of bacterial, fungal or viral infections. We observed only one case of CMV-related HPS (1/103; 0.9%) after autologous stem cell transplantation. Four patients died despite aggressive supportive care. To our knowledge, this is the first prospective observational study conducted with the aim to evaluate the incidence of HPS after HSCT. This study provides a relatively high incidence of HPS after ASCT. When sustained fever with progressive cytopenia and hyperferritinaemia are observed, HPS should be suspected, and bone marrow aspirate considered. The rapid diagnosis of HPS and the early initiation of an appropriate treatment are essential for patient management.

T1D after BMT constitutes a human model of autoimmune disease transmission. This case report refers to T1D onset after allogeneic HLA-matched BMT in a six-yr-old recipient affected by aplastic anemia. The donor was his sister who had T1D. The recipient had a complication free course apart from grade 1 acute GVHD, which was resolved spontaneously. With the predictive value and significance of T1D-associated autoantibodies, we tried to consolidate the T1D transfer possibility based on our patient characteristics and a literature review.

The aim of this study was to assess the impact of fractionated total body irradiation (F-TBI) on treatment-related mortality (TRM) and relapse in patients who received a non-T-cell-depleted allogeneic stem cell transplantation (ASCT) for hematological malignancies. Between March 2003 and December 2004, a total of 24 patients with HLA-identical sibling donors entered this study and received three doses of 3.33 Gy F-TBI separated by 24 h and cyclophosphamide or etoposide. At a median follow-up of 37 months (range 29–47 months), 4 of the 24 patients (16.6%) died of TRM. Relapse occurred in 10 patients at a median of 9 months (range 2–18 months). Overall, 13 of 24 patients (54%) died. Relapse was the most common cause of death (9/13). The 2-year actuarial survival rate was 46% (±11%). In our experience, ASCT conditioned with F-TBI was associated with low TRM but a high early relapse rate in patients with hematological malignancies.

We report an unusual case of a woman with acute myeloid leukemia who showed an isolated extramedullary relapse (IEMR) in the breast following allogeneic stem cell transplantation and review the related literature. Eighty cases of IEMR following allogeneic stem cell transplantation, including our case, were identified. The review suggests that an M2 or M4 phenotype in the French-American-British classification and a favorable cytogenetic risk group are more frequently associated with the occurrence of IEMR. Combined treatment with radiation and high-dose chemotherapy may be effective.

To describe the hematopoietic stem cell transplantation (HSCT) activities for children in the Eastern Mediterranean (EM) region, data on transplants performed for children less than 18 years of age between 1984 and 2011 in eight EM countries (Egypt, Iran, Jordan, Lebanon, Oman, Pakistan, Saudi Arabia and Tunisia) were collected. A total of 5187 transplants were performed, of which 4513 (87%) were allogeneic and 674 (13%) were autologous. Overall, the indications for transplantation were malignant diseases in 1736 (38.5%) and non-malignant in 2777 (61.5%) patients. A myeloablative conditioning regimen was used in 88% of the allografts. Bone marrow (BM) was the most frequent source of stem cells (56.2%), although an increasing use of PBSC was observed in the last decade. The stem cell source of autologous HSCT has shifted over time from BM to PBSC, and 80.9% of autologous HSCTs were from PBSCs. The donors for allogeneic transplants were matched-related in 94.5% of the cases, and unrelated transplants, mainly cord blood (99%) in 239 (5.5%) cases. This is the first report to describe the pediatric HSCT activities in EM countries. Non-malignant disorders are the main indication for allogeneic transplantation. Frequency of alternate donor transplantation is low.

Purpose Infection is a serious complication of central venous catheters in immunocompromised patients. Catheter-related infection may be caused by fibrin deposition associated with catheters. Interventions designed to decrease fibrin deposition have the potential to reduce catheter-related infections. The purpose of this study was to evaluate the role of low-dose unfractionated heparin in preventing catheter-related bloodstream infection in patients with hemato-oncological disease. Patients and Methods This study was a randomized, controlled trial in which patients with nontunneled catheters were randomly assigned to receive either intravenous unfractionated heparin (continuous infusion of 100 U/kg per day) or 50 mL/day of normal saline solution as a continuous infusion (control group). Heparin was continued until the day of discharge. Catheter-related bloodstream infection was defined according to Infectious Disease Society of America guidelines. Results Two hundred and eight patients were randomly assigned. Four patients were excluded after assignment. Ultimately, 204 patients were analyzed. Catheter-related bloodstream infection occurred in 6.8% (7 of 102 catheters) of those in the heparin group (2.5 events per 1,000 days) and in 16.6% (17 of 102 catheters) of those in the control group (6.4 events per 1,000 days) (P = .03). No other risk factors were found for the development of catheter-related bloodstream infection. Four and five patients experienced severe bleeding in the heparin and control groups, respectively (P = .2). We did not observe heparin-induced thrombocytopenia. Conclusion The use of continuous infusion of low-dose unfractionated heparin (100 U/kg per day) can be a practical and economical approach to the prevention of catheter-related bloodstream infection in patients with hemato-oncological disease.

Neisseria mucosa, a Gram-negative diplococcus, is part of normal nasopharyngeal flora. We report a case of bacteremia caused by N. mucosa in a 50-year-old neutropenic patient suffering from non-secretory multiple myeloma stage IIIA. This case underscores that mostly nonpathogenic N. mucosa can cause bacteremia in neutropenic patients who developed mucositis after hematopoietic stem cell transplantation.

SummaryWe have conducted a prospective randomized controlled trial to evaluate the role of low-dose unfractionated heparin prophylaxis in preventing central venous line-related thrombosis in patients with haemato-oncological disease. Patients were randomly assigned to receive either prophylactic intravenous unfractionated heparin (continuous infusion of 100 IU/kg/daily) or 50 ml/daily of normal saline solution as a continuous infusion. CVLs were externalized, non tunneled, double lumen catheters. All CVLs were placed percutaneously by the same physician in the subclavian vein. Upper limb veins were systematically examined by ultrasonography just before, or < 24 hours after, catheter removal, and in case of clinical signs of thrombosis. One hundred and twenty-eight CVLs were inserted. Catheterrelated thrombosis occurred in 1.5% of the catheters inserted in patients of the heparin group, and in 12.6% in the control group (p = 0.03). No other risk factors were found for the development of catheter-related thrombosis. Two and three patients experienced severe bleeding in the heparin group, and in the control group, respectively (p = 0.18). There were no other side-effects clearly ascribable to the use of unfractionated heparin. This is the first prospective, randomized study, which shows that low-dose of unfractionated heparin is safe and effective to prevent catheter-related thrombosis in patients with haemato-oncological disease.

Background Although the equimolecular mixture of oxygen and nitrous oxide (EMONO) seems a good choice to relieve procedure-related pain in children, it has not been evaluated for insertion of central venous catheters in children. To assess the safety and the effectiveness of this gas mixture for insertion of central venous catheters, we conducted a prospective observational study. Procedure This study was performed by the “Centre National de Greffe de Moelle Osseuse.” Procedure and inhalation characteristics, as well as pain evaluations and side effects, were reported. Results Fifty central venous catheters were inserted in 50 consecutive children. Median age was 7 (range, 4–13) years. An anesthesiologist was responsible for delivering EMONO, and provided constant surveillance throughout the procedure. EMLA cream was applied 2 hr before EMONO inhalation. No associated drugs were used. All catheters were inserted by the same experienced physician in the operating theater. Median inhalation length was 5 min (range, 3–6) before starting catheter's insertion and 12 min (range, 9–25) for the total inhalation. Median procedural pain evaluations were 10 (range, 0–30) for children on a 0–100 visual analog scale (VAS). Minor side effects were observed during eight (16%) inhalations. These side effects were euphoria (14%), deep sedation (4%), nausea and vomiting (2%), hallucinations (2%). All side effects were transient and resolved within 5 min after removing the inhalation device. Conclusions This study which shows that EMONO is effective for insertion of central venous catheters in children and represents a simple and safe alternative to general anesthesia. Pediatr Blood Cancer 2004;43:777–779. © 2004 Wiley-Liss, Inc.

Introduction Mesenchymal stem cells (MSCs) are multipotent cells able to differentiate into several mesenchymal lineages, classically derived from bone marrow (BM) but potentially from umbilical cord blood (UCB). Although they are becoming a good tool for regenerative medicine, they usually need to be expanded in fetal bovine serum (FBS)-supplemented media. Human platelet lysate (HPL) has recently been proposed as substitute for safety reasons, but it is not yet clear how this supplement influences the properties of expanded MSCs. Methods In the present study, we compared the effect of various media combining autologous HPL with or without FBS on phenotypic, proliferative and functional (differentiation, cytokine secretion profile) characteristics of human BM-derived MSCs. Results Despite less expression of adipogenic and osteogenic markers, MSCs cultured in HPL-supplemented media fully differentiated along osteoblastic, adipogenic, chondrogenic and vascular smooth muscle lineages. The analyses of particular specific proteins expressed during osteogenic differentiation (calcium-sensing receptor (CaSR) and parathormone receptor (PTHR)) showed their decrease at D0 before any induction for MSC cultured with HPL mostly at high percentage (10%HPL). The cytokine dosage showed a clear increase of proliferation capacity and interleukin (IL)-6 and IL-8 secretion. Conclusions This study shows that MSCs can be expanded in media supplemented with HPL that can totally replace FBS. HPL-supplemented media not only preserves their phenotype as well as their differentiation capacity, but also shortens culture time by increasing their growth rate.

In this article, we report a switch of beta-thalassemia major to intermedia beta-thalassemia after allogeneic bone marrow transplant of a 6-year-old girl from her HLA-matched brother. After stable mixed chimerism, the patient had a secondary graft rejection and returned to total recipient chimerism as assessed by real-time polymerase chain reaction assay. Nonetheless, with a medium hemoglobin rate of 89 g/L, she did not need further transfusions for 60 months after rejection. We conclude that complete loss of donor cells after bone marrow transplant for beta-thalassemia major is compatible with a stable clinical state, probably due to a gamma-globin gene demethylation that enhances gamma-globin chain production and further allows constitution of a fetal hemoglobin rate compatible with free transfusion survival.

GVHD is the major cause of mortality after HLA-identical HSCT. Such complication has been widely linked to donor/recipient disparity for minor histocompatibility antigens (MiHAgs). PECAM-1 is one of potential human MiHAgs but its effect on the GVHD occurrence remains not clear. In order to examine such association in the Tunisian cohort of HSCs recipients, we performed a retrospective study on patients who undergone HLA-identical HSCT between 2000 and 2009. Genotyping of the three selected PECAM-1 polymorphisms (rs668, rs12953 and rs1131012) was performed with SSP-PCR method. Univariate analyses showed that grades II–IV acute GVHD were considerably linked to the non-identity for rs12953 only in HLA-B44-like positive patients ( p = 0.010, OR = 10.000). Multivariate analysis for chronic GVHD showed that this outcome may be affected only by the adulthood and the conditioning regimen. Our findings support the previously reported data suggesting a significant association between the PECAM-1 disparity and the risk of acute GVHD.

Several centers are now performing allogeneic hematopoietic stem cell transplantation (HSCT) in the World Health Organization Eastern Mediterranean Region (EMRO) but the availability is still limited due to high cost and the need for multi-disciplinary team and an advanced laboratory support. Special issues including compatible donor availability, potential for alternate donor programs, differences in pattern of disease, pre-HSCT general status particularly for patients with BM failure, high sero-positivity for CMV, Hepatitis B and C infection and specific observations about GVHD with its relation to genetically homogeneous community are discussed. A total of 17 HSCT programs (performing five or more HSCTs annually) exist in nine countries of the EM region. Only six programs are currently reporting to EBMT or IBMTR. A total of 7617 HSCTs including 5701 allogeneic HSCTs have been performed. Due to low HSCT team density (1.5583 teams/10 million inhabitants versus 14.4333 in Europe) and very low HSCT team distribution (0.2729 teams/10,000 sq km area versus

Among the cases yet published of development of vitiligo after BMT, only two can claim as possible adoptive transfer of such disease. We report a case of a patient with sickle cell disease in whom vitiligo developed after allogeneic BMT from his HLA identical father affected by vitiligo. We reviewed and searched for some particularities in the reported cases of post-BMT vitiligo.

OS is a non-SCID immunodeficiency characterized by a poor outcome even after BMT. We report here a case of BMT without preparative conditioning regimen, and with a successful engraftment in a five-month-old infant with OS. The patient was transplanted with 15 × 108 bone marrow mononuclear cells/kg, from his HLA matched brother, without preparative regimen and GVHD prophylaxis. Immunological status was assessed before and after the BMT, and the engraftment was monitored with microchimerism analysis. Six days after BMT, an acute GVHD involving first the skin, then the liver and gut, complicated the post-transplantation course. An excellent engraftment was confirmed by donor chimerism over 95% respectively at day post-transplantation 30, 60, 90, and 150. The cellular immunity of the patient was restored, and infectious complications decreased after BMT. Later the patient experienced chronic GVHD, and he died on day post-transplantation 246 from GVHD. BMT without conditioning regimen for OS is feasible, but there must be a megadose cell transplantation, and appropriate prophylactic immunosuppressive treatment to prevent acute GVHD.

Bloodstream infections related to the use of central venous catheters are an important cause of patient morbidity, mortality, and increased health care costs. Catheter-related infection may be due to fibrin deposition associated with catheters. Interventions designed to decrease fibrin deposition have the potential to reduce catheter-related infections. This study was a randomized, controlled trial in which 246 patients with nontunneled central venous catheters were randomly assigned to receive a heparin-coated catheter with 50 mL/d of normal saline solution as a continuous infusion (heparin-coated group) or a noncoated catheter with a continuous infusion of low-dose unfractionated heparin (control group: continuous infusion of 100 U/kg/d). Catheter-related bloodstream infection occurred in 2.5% (3/120 catheters) in the heparin-coated group (0.9 events per 1,000 days) and in 9.1% (11/120 catheters) in the control group (3.5 events per 1,000 days; P = 0.027). No other risk factors were found for the development of catheter-related bloodstream infection. Six and seven patients experienced severe bleeding in the heparin-coated and control groups, respectively (P = 1.00). We did not observe heparin-induced thrombocytopenia. The use of heparin-coated catheters can be a safe and effective approach to the prevention of catheter-related bloodstream infection in patients with hematooncologic disease.

In the present study we report the clinical outcome of 27 patients with refractory or relapsed Hodgkin's lymphoma (HL) undergoing autologous peripheral stem-cell transplantation (ASCT).On transplant, 18 patients had sensitive disease (SD) and 9 resistant disease (RD). The median time between diagnosis and ASCT was 18 months (range, 7 to 96 months). The conditioning consisted of BEAM regimen.The 100-day mortality rate was 3%. Three months after transplant, 12 patients transplanted with SD were in complete remission (CR) and only one of the 9 patients transplanted with RD achieved CR. Overall survival and disease-free survival after 3 years were 68% and 60%, respectively.the present results confirm the efficacy and safety of the ASCT in refractory or relapsed HL patients with SD. Other strategies should be investigated for patients with RD.

A 55-year-old man with multiple myeloma developed sustained bleeding after bone marrow aspiration and cutaneous bleeding. Routine coagulation studies revealed a prolonged activated partial thromboplastin time and thrombin time (> 60 s) with a normal reptilase time. Further evaluation showed failure of the activated partial thromboplastin time to correct completely in a 1: 1 mixture with normal plasma. Treatment of the patient's plasma in vitro with protamine sulfate normalized the thrombin time. The presence of a heparin-like anticoagulant was suspected. The plasma heparin level was 0.73 IU/ml. Intravenous infusion of protamine sulfate appeared to neutralize the anticoagulant activity and stop the bleeding. The cancer cells themselves or the invasive nature of this type of cancer might result in a massive release of a heparinoid. Such coagulopathy appears to be a rare mechanism of bleeding and it is an important entity to consider since it is potentially reversible with protamine sulfate.

We report on the effectiveness of molecular studies regarding Fanconi anemia (FA) for a better selection of bone marrow graft donors and for post-transplant follow up. Ten unrelated FA patients and their families were analyzed by microsatellite markers. In 9 cases, the cytogenetic investigation of potential human leukocyte antigen (HLA)-identical related donors was normal, and the molecular analyses confirmed that they were also either normal or heterozygous carriers. For 1 patient, cytogenetic analysis of an HLA-identical sibling donor yielded ambiguous results with a relatively high number of chromosomal breakages using cross-linking agents. However, genotyping of this potential donor demonstrated his heterozygous state. Nine patients have received allogeneic bone marrow transplantation from HLA-matched related donors. Microsatellite analysis showed complete chimerism (CC) in all cases. The median follow up was 54 months (range 8-144 months). One patient out of 9 with CC rejected her graft without prior detection of a transitional mixed chimerism. Among these patients, 1 died 25 months after the transplantation of a chronic graft-versus-host-disease (GVHD). We conclude that, when the cytogenetic studies are not conclusive, molecular analyses are crucial to distinguish heterozygous carriers from asymptomatic FA Tunisian patients. Molecular analyses also allowed the evaluation of hematopoietic chimerism after allogeneic bone marrow transplantation and might be of value to identify patients with a high risk for graft rejection.

We describe a case of Plasmodium falciparum infection in a 25-year-old male patient with a myelodysplastic syndrome, who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) in September 2003. Conditioning regimen consisted of total body irradiation (10 Gy) and cyclophosphamide 60 mg/kg for 2 days. A dose of 4 � 10 6 CD34 þ cells/kg was transfused. Engraftment was well documented on day 17 post-transplantation. Spiking fevers occurred on days 19 and 21, associated with a pancytopenia, hepatosplenomegaly and neurological signs. P. falciparum parasites were found on the peripheral blood smear (parasitemia ¼ 23%). Marrow aspiration showed P. falciparum parasites and proliferation of mature histiocytes with hemophagocytosis. Quinine 10 mg/kg i.v. three times a day for 10 consecutive days was given. The fever subsided within 3 days, and pancytopenia vanished in 14 days. Parasitemia cleared in 6 days. The patient left the unit on day 46 with no further complications. The screening of donors showed that infection was acquired from two blood units (from a single donor) given 5 days before transplantation. We report the first case of profound hemophagocytosis in immunosuppressed patient with malaria of high parasitemia after a bone marrow transplant. The Hematology Journal (2004) 5, 449–450. doi:10.1038/sj.thj.6200531

Although the equimolecular mixture of oxygen and nitrous oxide (EMONO) seems a good choice to relieve procedure-related pain in children, it has not been evaluated for insertion of central venous catheters in children. To assess the safety and the effectiveness of this gas mixture for insertion of central venous catheters, we conducted a prospective observational study.This study was performed by the "Centre National de Greffe de Moelle Osseuse." Procedure and inhalation characteristics, as well as pain evaluations and side effects, were reported.Fifty central venous catheters were inserted in 50 consecutive children. Median age was 7 (range, 4-13) years. An anesthesiologist was responsible for delivering EMONO, and provided constant surveillance throughout the procedure. EMLA cream was applied 2 hr before EMONO inhalation. No associated drugs were used. All catheters were inserted by the same experienced physician in the operating theater. Median inhalation length was 5 min (range, 3-6) before starting catheter's insertion and 12 min (range, 9-25) for the total inhalation. Median procedural pain evaluations were 10 (range, 0-30) for children on a 0-100 visual analog scale (VAS). Minor side effects were observed during eight (16%) inhalations. These side effects were euphoria (14%), deep sedation (4%), nausea and vomiting (2%), hallucinations (2%). All side effects were transient and resolved within 5 min after removing the inhalation device.This study which shows that EMONO is effective for insertion of central venous catheters in children and represents a simple and safe alternative to general anesthesia.

Extramedullary plasmocytoma (EMP) is a rare cell neoplasm most frequently localised in the upper respiratory tract. We report the case of a 43 year-old-man, with an unusual presentation of EMP developing in the mediastinum, two years after a diagnosis of solitary plasmocytoma of the bone which was successfully treated by local irradiation. In this aggressive presentation, we decided to perform an autologous hematopoietic stem cell transplantation. Two months after transplantation, CT scan showed disappearance of the mediastinal mass and immunofixation of the serum was normal. Selected cases of diffuse EMP, could benefit from intensive treatment followed by autologous hematopoietic stem cell transplantation.

Background. Inadequate reconstitution of CD4 + lymphocyte and interleukin (IL)-2 production defect are observed after bone marrow or peripheral blood stem cell transplantation (SCT). Methods. We studied immune reconstitution after SCT in 33 consecutive patients who received allogeneic SCT (17 patients) or autologous SCT (16 patients). The aims were to assess the regeneration of the CD4 + T-cell subset with regard to helper cell differentiation. CD4 + T-cell subset regeneration and expansion of the CD4 + CD7 - subset were studied by immunofluorescence analysis. CD4 + CD7 - cell cytokine secretion was analyzed after cell sorting and costimulation of the CD3 and CD28 pathways, in enzyme-linked immunosorbent assay and reverse transcription-polymerase chain reaction assays. Results. We report a relative expansion of the CD4 + CD7 - subset within CD4 + T cells, detected as early as 1 month after bone marrow transplantation and decreasing after day 60. CD4 + CD7 - T cells preferentially expressed CD45RO and activation markers such as CD57, CD25, and HLA-DR. No relationship was observed between the CD4 + CD7 - expansion and transplant-related complications. We observed no significant IL-2 production in supernatants from sorted CD4 + CD7 - T cells, whereas IL-4 levels were comparable to those produced by cells from normal individuals. Autologous CD4 + CD7 + cells showed little, if any, IL-4 production, and IL-2 production was lower than that by normal CD4 + CD7 + T cells. Reverse transcription-polymerase chain reaction assays showed similar amounts of interferon-γ transcripts in the two subsets; tumor necrosis factor-α, IL-4, and IL-10 transcripts were detected in CD4 + CD7 - T cells but not in their CD4 + CD7 + counterparts. Conclusions. These data confirm the IL-2 production defect after bone marrow transplantation and suggest that the CD4 + CD7 - T-cell subset might be preferentially involved in the enhanced production of IL-4 and low production of IL-2. These data show that the early immune reconstitution in CD4 + T cells after SCT preferentially involves memory T cells with a Th0/Th2 differentiation that might participate in the T-helper cell defect.

Abstract 4648 Objectives A central venous access is always necessary for the management of patients receiving myeloablative conditioning followed by allogeneic stem cell transplantation (SCT). Tunnelled, cuffed silastic catheters are the device of choice for these patients. To our knowledge, there are no prospective studies investigating the use of totally implantable central venous access ports (TIAP) in patients receiving myeloablative conditioning followed by allogeneic SCT. The aim of this prospective study was to investigate the usefulness of a new “high flow” single lumen port device in these patients. <>Methods: Between December 2007 and July 2009, patients with haematological malignancies received a TIAP prior to allogeneic SCT. All patients received the same type of port [silicone, 10 French, high flow rate (3100ml/h), Reference 40010, Laboratoires Perouse, Ivry le Temple, France]. All devices were inserted under local anesthesia through direct puncture of the right subclavian vein using the Seldinger technique. A chest X-ray was always obtained to document correct positioning. All infusions, including the graft itself and all blood drawings, were performed via the port. Port-related bloodstream infection was defined according to Infectious Disease Society of America guidelines. All patients were examined by ultrasonography in case of clinical signs of thrombosis and systematically after discharge. Results Forty six TIAP were placed in 46 patients [median age: 25 years (20-41 years); 20 female and 26 male], and remained in place for a cumulative duration of 9756 days in situ (range 30-560 days). No pneumothorax occurred. Port-related bloodstream infection occurred in 2 cases (candida parapsilosis and staphylococcus aureus) [2/46, 4.3% ; 0.2 event per 1000 days]. These ports were removed. No port-related thrombosis occurred. No port-related deaths were observed. In conclusion, the use of “high flow” totally implantable ports has resulted in a good option for long-term access to central veins and delivery of myeloablative conditioning followed by allogeneic SCT, in spite of severe neutropenia and increased risk of sepsis in this category of patients. Although multicentre randomized clinical trials are needed to define the optimal device in this clinical setting, the results of this prospective study support the wider use of TIAP in patients receiving myeloablative conditioning followed by allogeneic SCT. Disclosures: No relevant conflicts of interest to declare.

Central venous catheters (CVCs) are widely used in patients with hemato-oncological disease for indications such as administration of chemotherapy, parenteral nutrition, blood products and monitoring of hemodynamics. CVCs are a major source of hospital-acquired infection. The National Nosocomial Infections Surveillance System reported a rate of catheter-related bloodstream infection (CRBI) of five per 1000 central catheter-days. This study was a randomized trial in which patients with nontunneled catheters were randomly assigned to heparin-coated (7 French, polyurethane, double lumen; Arrow®, USA) or chlorhexidine and silver sulfadiazine impregnated CVCs (7 French, polyurethane, double lumen; Arrow®, USA). All CVCs were placed in the subclavian vein in the operating room. CRBI was defined according to Infectious Disease Society of America guidelines. The principal investigator determined whether infections were catheter related and had no knowledge of “the assigned arm” at the time of adjudication of the reference standard definition. Before catheter insertion, laboratory prothrombotic markers included factor V Leiden, the prothrombin gene Gly20210A mutation, plasma antithrombin levels, and protein C and S activity. In our study, all patients were systematically examined by ultrasonography just before, or less than 24 hours after, catheter removal and in case of clinical signs of thrombosis. Two radiologists performed the ultrasonography and were unaware of the allocation of the patients. Two hundred and twenty patients were randomly assigned. Eight patients were excluded after assignment. Ultimately, 212 patients were analyzed [median age: 28 years (7–60); 97 female and 115 male]. CRBI occurred in 6.7% (7/104) of those in the heparin-coated group (2.7 events per 1000 days) and in 4.6% (5/108) in the chlorhexidine and silver sulfadiazine group (2 events per 1000 days) (P=0.5). The microorganisms involved in CRBIs were coagulase-negative Staphylococcus (five cases in the heparin group and 3 cases in the antiseptic group), Staphylococcus aureus (one case in the heparin group), Candida parapsilosis (one case in the antiseptic group), Pseudomonas aeruginosa (one case in the heparin group and one case in the antiseptic group). We observed a CVC-related thrombosis in 11 patients (5.2%; 5 in the heparin group and 6 in the antiseptic group P=0.8). Catheter-related thrombosis and CRBI coincided in two patients and were not significantly correlated (P=0.6). Four (1.9%) and three (1.4%) patients had evidence of protein C and protein S deficiency, respectively. Only one patient had an antithrombin deficiency (0.5%). In total, 9 patients (4.2%) were heterozygous for the factor V Leiden mutation. Thrombosis was diagnosed in three out of 17 patients (17.6%) with a inherited prothrombotic abnormality compared to 8 out of 195 patients (4.1%) who did not have a thrombophilic marker (relative risk 4.3 CI 95% 1.2–14.7). Six and five patients experienced severe bleeding in the heparin and antiseptic groups, respectively. We did not observe heparin-induced thrombocytopenia and anaphylaxis to chlorhexidine was not reported. To our knowledge, this is the first randomized study comparing in haematological patients heparin-coated with antiseptic impregnated CVCs. Furthermore, our results suggest that inherited prothrombotic abnormalities contribute substantially to CVC-related thrombosis in hemato-oncological patients. Presently, the best options for reducing CRBI are heparin-coated and antibiotic-impregnated CVCs. A large, well designed randomized controlled trial is required to determine which of these is most effective.

Background: Thalidomide which represents an effective treatment strategy for relapsed/refractory multiple myeloma, actually represents a standard of care also for newly diagnosed multiple myeloma patients. Methods: In the present study, we adopted a gene expression profiling (GEP) strategy in an attempt to predict response (> 50% reduction in serum M protein) to primary therapy with thalidomide-dexamethasone for newly diagnosed multiple myeloma. Plasma cells (CD138+) were purified from bone marrow aspirates from 17 patients at diagnosis, before initiation of treatment with thalidomide-dexamethasone. GEP was performed using the Affymetrix U133 Plus_2 microarray platform. The Affymetrix output (CEL files) was imported into Genespring 7.3 (Agilent technologies) microarray analysis software, where data files were normalized across chips using GCRMA and to the 50th percentile, followed by per gene normalization to median. Criteria of response were those established by Bladè et al. Results: After sufficient follow-up, responders (n=9) and nonresponders (n=8) were identified, and gene expression differences in baselines samples were examined. Of the 11000 genes surveyed, Wilcoxon rank sum test identified 149 genes that distinguished response from non response. A multivariate step-wise discriminant analysis (MSDA) revealed that 14 of the 149 genes could be used in a response predictor model (see table). Of interest, the gene list encompasses WXSC1, known to be involved in the chromosomal translocation t(4;14) (p16.3;q32.3) in multiple myeloma. Conclusion: These results could be the first step to adopt microfluidic cards, in an attempt to select at diagnosis patients who will respond favourably to a particular treatment strategy. List of 14 genes able to predict response to primary therapy with thalidomide-dexamethasone for newly diagnosed multiple myeloma. Gene ID Gene Name Chromosomal location 212771_at C10orf38 10p13 229874_x_at LOC400741 1p36.13 219690_at U2AF1L4 19q13.12 202207_at ARL7 2q37.1 243819_at GNG2 14q21 203753_at TCF4 18q21.1 235400_at FCRLM1 1q23.3 211474_s_at SERPINB6 6p25 226785_at ATP11C Xq27.1 215440_s_at BEXL1 Xq22.1–q22.3 209054_s_at WXSC1 4p16.3 227168_at FLJ25967 22p12.1 213355_at ST3GAL6 3q12.1 223218_s_at NFKBIZ 3p12–q12

Background: Autologous stem cell transplantation (ASCT) is now considered standard therapy in young patients ( Methods: From May 2003 to April 2006, 140 patients with symptomatic MM (de novo) and less than 60 years of age, were randomly assigned to receive either tandem transplantation up-front (within 6 months of the first transplantation) [Arm A, n=69] or one ASCT followed by a consolidation therapy with thalidomide (day +90, 100 mg/per day during 5 months) [Arm B, n=71]. Patients included in the arm B received a second transplant in case of disease progression on consolidation therapy, or in case of relapse in responders. Clinical characteristics of each group were similar. In both arms of the study, ASCT was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m2) and G-CSF. Data were analyzed on an intent-to-treat basis. Results: With a median follow-up of 23 months (range: 6–34), the 2-year overall survival was 55% in the arm A and 75% in the arm B. Survival curves were not different (P=0.28, log-rank test). The 2-year event-free survival was 41% in the arm A and 60% in the arm B (P=0.4, log-rank-test). In the arm B, relapse-free survival of ≥ 16 months following the first transplantation was an important predictor of overall survival (p< 0.001). Conclusion: Data from the present study suggest that up-front single ASCT followed by a consolidation therapy with thalidomide and a second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients. Longer follow-up is needed before definite conclusions can be given concerning the optimal timing of second autologous transplantations in patients with MM.