WORKING PARTIES

Acute Leukemia While the positive impact of RIC allo-SCT in terms of NRM reduction has been well established, the putative higher incidence of disease relapse after RIC allo-SCT has been a major mater of concern. Therefore, many investigators were not keen to WP001 propose RIC allo-SCT strategies for those patients who could Genotypes and their impact on upfront and postremission tolerate a standard or conventional myeloablative conditioning treatment strategies (MAC). However, the advent of novel conditioning regimens R. F. Schlenk1,* including purine analogs combined with myeloablative doses of 1Internal Medicine III, University of Ulm, Ulm, Germany drugs such as IV busulfan, thiotepa, and ATG proved to be safe (lower NRM) and effective in high risk patients with acute Genetic heterogeneity is one hallmark of acute myeloid leukemia towards optimizing outcome. With this background, the leukemia (AML). Disease classification, prognostication and field is currently moving progressively from the so-called non- prediction are based on the cytogenetic but even more and myeloablative RIC regimens to a more comprehensive approach more important on the molecular profile of the disease. As focusing on Reduced Toxicity Conditioning (RTC) regimens. This promising molecularly targeted therapeutics and early allo- review will aim to address some of the practical issues related to geneic transplant strategies in selected risk-constellations the use of RTC allo-SCT in acute leukemia patients, including becoming available fast pre-therapeutic molecular screening some perspectives in the haplo-mismatch setting. at diagnoses including fusion genes such as PML-RARA, RUNX1- Disclosure of Interest: None declared. RUNX1T1 and CBFB-MYH11 as well as gene mutations such as NPM1, FLT3, CEBPA and TP53 are increasingly performed in WP003 routine care. The identification of the genetic determinants of AutoSCT for acute leukemia-revisited:reducing TRM response to standard but also to experimental treatment is by IV Bu based conditioning used for patient counseling, to guide clinical decisions A. Nagler1,* on behalf of ALWP making at diagnosis, during consolidation treatment and 1Hematology Division and Bone Marrow Transplantation, Chaim follow-up as well as after relapse. In addition, the pre-treatment Sheba Medical Centre, Ramat Gan, Israel risk-defining parameters have been supplemented by markers evaluated at distinct time points during treatment and follow Autologous stem cell transplantation (AutoSCT) is an effective up. In this context, residual disease assessment is increasingly therapeutic modality for adults with acute leukemia. Many used to dynamically fine tune treatment recommendations. randomized studies have demonstrated lower relapse inci- Once a complete remission of the disease is achieved after dence following AutoSCT compared to chemotherapy and induction therapy, the gold standard to counterbalance a lower transplant related mortality (TRM) and better quality of higher risk of relapse by treatment strategies based on life (QoL) compared to allogeneic SCT. However, due to the hematopoietic stem cell transplantation (HSCT) with grafts development of reduced intensity and reduced toxicity from matched related or unrelated donors is still valuable, preparative regimens for allogeneic transplants over the last whereas autologous hematopoietic stem cell transplantation 15 years, the number of AutoSCTs in Europe has drastically showed promising results especially in patients categorized as declined. Recent developments including the use of targeted low-risk. Nonetheless, more targeted approaches in combina- therapy like tyrosine kinase inhibitors (TKI) pre or post- tion with or sequentially before or after intensive chemother- AutoSCT for ALL, better techniques for detection and apy and/or allogeneic HSCT are currently in clinical evaluation monitoring of minimal residual disease (MRD) pre and post- and may lead to more targeted- instead of purely risk-adapted transplant and the use of new compounds and new drug treatment strategies. formulations (like intravenous busulfan) may improve AutoSCT Disclosure of Interest: None declared. outcome. These developments make AutoSCT an attractive option for elderly patients with AML and in particular those WP002 with good risk and some of those with intermediate risk From Reduced Intensity to Reduced Toxicity leukemia. We have recently analyzed, within the ALWP of the Conditioning EBMT the outcomes of 952 AML patients who underwent M. Mohty1,* on behalf of Acute Leukemia Working Party AutoSCT with intravenous busulfan-based conditioning, rather 1Hematology Dpt., Hopital Saint-Antoine, Paris, France than with oral busulfan, the historical backbone of pre transplant conditioning. 531 (56%) were male and the median In the last decade, the so-called reduced intensity conditioning age at transplantation was 50.5 years. Two-year overall (RIC) regimens prior to allogeneic stem cell transplantation survival, leukemia-free survival, and relapse incidence were (allo-SCT) have emerged as an attractive modality to decrease 67±2%, 53±2%, and 40±2%, respectively. The non-relapse allo-SCT-related toxicities and non-relapse mortality (NRM). mortality rate at 2 years was 7±1%. Five patients died of Indeed, RIC allo-SCT represents an attempt to harness the veno-occlusive disease of the liver. Overall leukemia-free immune graft-versus-tumor (GVT) effect while attempting to survival and relapse incidence at 2 years did not differ control or overcome toxicity. The work of different pioneering significantly between the 815 patients transplanted in the first groups rapidly proved that this approach is feasible in several complete remission (52±2% and 40±2%, respectively) and disease settings or patients’ categories, and had the added the 137 patients transplanted in the second complete benefit of expanding the transplant option to patients who are remission (58±5% and 35±5%, respectively). Cytogenetic ineligible for standard myeloablative allo-SCT. Currently, an risk classification and age were significant prognostic factors increasing number of studies are addressing the specific role for transplant outcomes. The 2-year leukemia-free survival was and potential benefits of RIC allo-SCT versus other treatment 63±4% in patients with good risk cytogenetics, 52±3% in strategies. However, the RIC approach proved to be much those with intermediate risk cytogenetics, and 37±10% more complex than originally thought. in those with poor risk cytogenetics (P ¼ 0.01). Patients

S97 r50 years old had better overall survival (77±2% versus reduce the risk of disease recurrence broadly consist of 56±3%; Po0.001), leukemia-free survival (61±3% versus intensification of the conditioning regimen, without a 45±3%; Po0.001), relapse incidence (35±2% versus 45±3%; concurrent increase in toxicity, and optimisation of a graft- Po0.005), and non-relapse mortality (4±1% versus 10±2%; versus-leukaemia (GVL) effect. The great majority of patients Po0.001) than older patients. The combination of intravenous who are destined to relapse post-transplant do so within the busulfan and high-dose melphalan was associated with the first 12 months post-transplant and consequently strategies best overall survival (75±4%). These results suggest that the aimed at augment a GVL effect must be implemented early if use of intravenous busulfan simplifies the autograft procedure they are to be of clinical relevance. Epigenetic therapies, such and confirm the usefulness of AutoSCT in AML. As in as DNA methyltransferase inhibitors have been shown to up- allogeneic transplantation, veno-occlusive disease is an regulate the expression of epigenetically silenced putative uncommon complication after an autograft using intravenous tumour antigens and also hasten T regulatory cell reconstitu- busulfan. Based on these and other recently published data, tion post allograft. In a recent EBMT ALWP study the DNMTi the role of AutoSCT in acute leukemia should be revisited. azacitidine (AZA) was shown to possess significant clinical Disclosure of Interest: None declared. activity in a cohort of 272 patients with AML and myelodys- plasia who had relapsed post alloSCT. Predictors of response to AZA included time to relapse post-transplant and presenta- WP004 tion karyotype. A scoring system including time to relapse, Strategies to prevent relapse following alloSCT for acute presentation karyoytpe and marrow blast percentage at the leukemia—the 2015 perspective time of relapse predicts CR rate and 2 year overall survival (OS) C. Schmid1,*, M. Labopin2,3, A. Mailhol2,4, E. Polge2,3, A. Nagler5 after AZA salvage. A number of small studies have demon- 1Department of Haematology and Oncology, Klinikum Augsburg, strated adjunctive AZA can be administered early after alloSCT University of Munich, Augsburg, Germany, 2Service d’He´matolo- and we therefore prospectively studied the impact of post- gie et The´rapie Cellulaire, Hopital Saint Antoine, 3Acute Leukemia transplant AZA on the incidence of disease relapse and GVHD Working Party of EBMT, 4Leukemia Working Party of EBMT, Paris, in 37 adults with high risk AML undergoing allogeneic SCT France, 5Hematology Division, Tel-Aviv University, Sheba Medical using an alemtuzumab based reduced intensity conditioning Center, Tel-Hashomer, Israel regimen. AZA was administered at a dose of 36 mg/m2 for five consecutive days at four weekly intervals until 12 months post- Introduction: Relapse after allogeneic stem cell transplanta- transplant. AZA was commenced at a median of 54 days tion (HSCT) for acute leukemia remains the leading course of (range 40–194 days) post-transplant and was well tolerated in treatment failure. No standard treatment has been established the majority of patients. 16 patients relapsed at a median time so far, and results are unsatisfying. Hence, novel and of 8 months post-transplant. No patient developed extensive innovative strategies to prevent hematological relapse are in chronic GVHD. AZA induced a CD8 þ T cell response to one or real need being essential for improvement. more tumor-specific peptides in 16 patients. Induction of a Materials (or patients) and methods: These approached may CD8 þ T cell response was associated with a reduced risk of be divided into pre-, intra- and post HSCT strategies. disease relapse (P ¼ 0.02) and improved relapse free survival Results: Among the first, achieving a better quality of (P ¼ 0.02) at one year post-transplant. These observations remission before pre HSCT conditioning by introduction of require confirmation in a randomised prospective clinical trial. novel, ideally disease-specific drugs in combination with In conclusion hypomethylating agents represent an important modern molecular techniques for monitoring clinical response novel salvage therapy in selected patients who have relapsed and detection of minimal residual disease is a promising post alloSCT and demonstrate initial promise when adminis- approach. During the transplant phase, modification of both tered immediately post-transplant as a strategy to reduce the the conditioning and the prophylactic immune suppressive risk of disease relapse in patients transplanted for high risk medication, as well as purposeful choice of donor and graft AML. source represent other possibilities to reduce the risk of Disclosure of Interest: None declared. relapse. Finally, in the post-transplant phase, maintenance strategies intend to prevent relapse, either by methods that are based on the allo-immune reaction (early discontinuation of immunosuppression, transfusion of donor lymphocytes or Severe Aplastic Anemia other immunocompetent cell subsets), or by applying novel drugs such as thyrosine kinase inhibitors or epigenetic modifiers. Current studies address both purely prophylactic strategies (i.e. treatment without any evidence of disease, WP006 ususally applied in high-risk disease), or preemptive action, Lymphoproliferative disorders associated to AA driven by detection of decreasing donor chimerism or A. Rovo1,*, R. Peffault de Latour2, C. Knol3, P. Chevallier4, molecular relapse. Recently, specific chimeric antigen-receptor B. Benedetto5, J. Apperley6, M. Koh7, H. Schouten8, W. Blau9, (CAR) T-cells (mainly in lymphatic malignancies) and vaccina- A. Tichelli10, A. Kulasekararaj11, A. Risitano12, J. Passweg10, tion strategies have been introduced to prevent relapse or to P. Dreger13, C. Dufour14 on behalf of SAAWP treat leukemic recurrence already at the molecular level. 1University Hospital of Bern, Bern, Switzerland, 2Hopital St. Louis, Conclusion: An overview on current strategies addressing Paris, France, 3EBMT Data Office, Leiden, Netherlands, 4CHU prevenmtion of acute leukemia relapse after allogheneic SCt Nantes, Nantes, France, 5A.O.U Citta della Salute e della Scienza will be presented di Torino, Torino, Italy, 6Imperial College, 7St. George`s Hospital, Disclosure of Interest: None declared. London, United Kingdom, 8University Hospital Maastricht, Maastricht, Netherlands, 9Charite´—Campus Benjamin Franklin, Berlin, Germany, 10University Hospital of Basel, Basel, Switzerland, WP005 11King`s Denmark Hill Campus, London, United Kingdom, Are we changing the scope of AML (Acute Myeloid 12University of Napoli, Napoli, Italy, 13University of Heidelberg, Leukaemia) relapse post allogeneic stem cell Heidelberg, Germany, 14Institute G. Gaslini, Genova, Italy transplantation (AlloSCT) by hypomethylating agents? C. Craddock1,* 1 Introduction: Association between aplastic anemia (AA) and Haematology, University of Birmingham, Birmingham, United lymphoid neoplasms is unusual and represent a challenge. We Kingdom do not yet know whether there is causality in this association or simply coincidence. Data related to frequency, diagnosis Disease relapse remains the major cause of treatment failure in and management of patients with such an association are patients allografted for AML. Strategies with the potential to lacking. The SAAWP of the EBMT aimed to collect information

S98 of patients with AA and a lymphoid neoplasm according two- The Severe Aplastic Anaemia Working Party (SAAWP) has step procedures. started a large multicenter, multinational, study to investigate Material and methods: First, a search for this association was the possible benefit of eltrombopag once added to the performed within the registry of the EBMT. Patients who backbone of frontline standard IST, i.e. horse-ATG (ATGAM, developed either AA or lymphoma after hematopoietic stem Pfizer) and CsA, with the goal of providing a new standard of cell transplantation (HSCT) were excluded for this analysis, care for AA patients. The RACE trial is an EBMT study, co- because bone marrow failures emerging after HSCT may funded by pharmaceutical companies which will cover all the represent the loss of the graft, and the occurrence of a costs and will provide the main drugs utilized in the study. The lymphoma after HSCT represents a complication of the primary objective of the study is to improve the rate of transplantation, the so-called post-transplant lymphoproliferative complete response at 3 months; according to the statistical disorder. Both situations do not belong to the scope of this study. design, 200 SAA patients (100 each arm) will be enrolled. The In a second step, centers who reported a case were asked for recruitment of patients is just started, and it is anticipated that more detailed information concerning type of therapy and it will last 36 months. The EudraCT number of the study is outcome for each disease. Since we hypothesize an under- 2014-000363-40, and it is registered on the NCT website reporting of such association in non-severe AA, centers (http://clinicaltrial.gov/show/NCT02099747). reporting AA patients to the EBMT registry were contacted Disclosure of Interest: None declared. and asked to inform about any additional case with such an association. WP008 Results: So far, we detected 8 cases reported by 7 different Thymoglobulin or Campath for HSCT in SAA centers (202 ¼ 1; 205 ¼ 1; 231 ¼ 1; 253 ¼ 2; 539 ¼ 1; 565 ¼ 1 1,* 2 3 4 and 590 ¼ 1) from 6 different countries within the EBMT S. Samarasinghe , C. Dufour , J. Marsh , A. Risitano on behalf of EBMT SAA WP registry. Four patients were treated with HSCT after both 1 diagnoses, and 4 patients were treated with immunosuppres- Paediatric Haematology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom, sion therapy (IST) for AA. In 5 cases the AA was the first 2 diagnosis, and lymphoma was diagnosed afterwards. Time Pediatric Hematology, Giannina Gaslini Children’s Hospital, Genova, Italy, 3Department of Haematology, King’s College between both diagnoses was shorter than 1 year in three 4 cases (4, 9 and 11 months), and longer in 2 cases (36 and 84 Hospital, London, United Kingdom, Department of Haematol- months). Three cases had an initial diagnosis of lymphoma ogy, Haematology, Department of Biochemistry and Medical and many years later developed AA (4, 12 and 36 years). All 8 Biotechnologies, Federico II University of Naples, Naples, Italy patients were diagnosed with a non-Hodgkin lymphoma (diffuse large B-cell lymphoma ¼ 3; follicular lymphoma ¼ 1, Haematopoietic stem cell transplantation (HSCT) from a without further information available ¼ 4). Patients treated matched sibling donor (MSD) using high dose cyclopho- with IST had a median survival of 81 months (54-123), all were sphamide (200 mg/kg) and ATG (Cy/ATG) is the treatment of alive with remission of both diseases at last control. 3 out of 4 choice for children and young adults with SAA, with survival patients who underwent an allogeneic HSCT were alive and in rates of 75-90%. However, graft rejection remains a problem in remission for both diseases at last control, median survival around 4-14%. Chronic GVHD occurs in around 30-40% and post-HSCT was 20 months (3-45). significantly impairs both overall survival and quality of life. Conclusions: This very preliminary data confirm the uncom- Chronic GVHD remains the most important adverse factor for mon association between AA and lymphoid neoplasms. This is long term survival following MSD HSCT for paediatric SAA. An an ongoing study, data collection will continue until February alternative approach is to use alemtuzumab instead of ATG 2015, an extended up-dated analysis will be presented during along with fludarabine and cyclophosphamide (FCC). In two the 41th Annual Meeting of EBMT. different MSD HSCT series, one using ATG (Cy-ATG) and the Disclosure of Interest: None declared. other alemtuzumab (FCC), there were similar outcomes in both except that chronic GVHD was less common in the alemtu- zumab arm (Table 1). A comparison of the two conditioning WP007 regimens (Fludarabine/Cyclophosphamide/ATG-FCA) and FCC The RACE study: a SAAWP prospective Randomized in the matched unrelated donor (MUD) HSCT setting also multicenter study comparing horse Antithymocyte suggests that alemtuzumab may reduce the incidence of globulin (hATG) þ Cyclosporine A (CsA) with or without chronic GVHD in the MUD setting compared to ATG. An Eltrombopag as front-line therapy for severe aplastic update on the UK experience of FCC and preliminary data on a anaemia patients EBMT comparison of ATG and Alemtuzumab in SAA HSCT will A. M. Risitano1,*, J. Marsh2, C. Dufour3, R. Peffault De Latour4 be presented. 1Federico II University of Naples, Naples, Italy, 2King’s College, London, United Kingdom, 3Ospedale Gaslini, Genova, Italy, 4Hopital St. Louis, Paris, France Table 1. Comparison of ATG vs. Alemtuzumab following Antonio M Risitano, Judith Marsh, Carlo Dufour and Regis MSD HSCT for idiopathic SAA. Alemtuzumab based Peffault De Latour; on behalf of the Severe Aplastic Anemia conditioning regimens were associated with low levels of Working Party. chronic GVHD. Immunosuppressive therapy (IST) is a standard treatment option for severe aplastic anaemia (SAA) patients not eligible CY-ATG Alemtuzumab for sibling bone marrow transplantation (BMT). However, no 2 3 improvement has been made in the past 20 years in the (n ¼ 68) (FCC) (n ¼ 21) setting of IST for SAA. Indeed, the standard IST for SAA remains the combination of anti-thymocyte globulin (ATG) and Time of HSCT 1994-2001 1999-2010 cyclosporine A (CsA), with a response rate of 60-70% (only Overall Survival 89% 95% when using horse-ATG preparations). Recently, the thrombo- Graft Failure 13.2% 9.5% poietin mimetic agent eltrompobag (150 mg per day, orally) Acute GVHD (II-IV) 11% 16.5% has been approved by the FDA for the treatment of AA Chronic GVHD 32% 4% patients refractory to IST, based on the NIH experience showing a 40% response rate of 44% (17 out of 43 cases) in this patient setting. Given its postulated effect on residual hematopoietic stem cells, eltrombopag may work synergisti- cally with IST, eventually improving its efficacy in SAA patients. Disclosure of Interest: None declared.

S99 WP009 disease that is in part independent from marrow failure Lung Outcome of bone marrow transplantation in diskeratosis involvement is a frequent cause of death thus (infections and congenita: preliminary data from the European Group for GvHD) suggesting that lung status may be weighted regarding Bone Marrow Transplantation the choice of HSCT. Future data comparing outcome of DKC F. Fioredda1,*, L. Korthof2, S. Iacobelli 3, C. Knol4, D. Ziagkos2, transplanted vs non transplanted patients will help to better J. Tolar5, A. van Biezen 2, J. H. Velken2, G. Socie´6, P. Veys7, understand the position of HSCT in the DKC treatment M. Aljurf8,R.Or9, J. de la Fuente 10, A. Bacigalupo11, A. Fisher12, algorithm. F. Fagioli13, J. S. de Toledo Codina14, M. Zecca15, Disclosure of Interest: None declared. A. Ghavamzadeh16, T. O’Brien 17, O. Smith18, C. Dufour1 1Istituto Giannina Gaslini, Genova, Italy, 2Leiden University 3 WP010 Medical Center, Leiden, Netherlands, Centro Interdipartimentale Horse ATG (ATGAM) and idiopathic aplastic anemia di Biostatistica e Bioinformatica, Rome, Italy, 4Leiden University 5 in France: response rates and long-term outcomes Center, Leiden, Netherlands, University of Minnesota, Minnea- 1,* 6 7 R. Peffault De Latour polis, United States, Hospital St Louis, Paris, France, Great 1BMT unit, Saint-Louis hospital, Paris, France Ormond Street Hospital Children’s Charity, London, United 8 Kingdom, 6 King Faisal Specialist Hospital & Research Centre, Idiopathic aplastic anemia (AA) is considered as an auto- Rhyad, Saudi Arabia, 9hadassah University Hospital, Jerusalem, 10 11 immune disorder. The standard first line treatment for a newly Israel, St Mary Hospital, London, United Kingdom, Ospedale diagnosed patient with AA and criteria for treatment (severe San Martino, Genova, Italy, 12Hopital Necker, Paris, France, 13 14 form of the disease or transfusions in case of moderate AA) is Ospedale Infantile Regina Margherita, Torino, Italy, Hospital allogeneic bone marrow transplantation (BMT) from an HLA- Vall d’Hebron, Barcelona, Spain, 15Fondazione IRCCS Polclinico 16 identical sibling donor if available. In the absence of a San Matteo, Pavia, Italy, Shariati Hospital, Teheran, Iran, matched family donor or if the recipient is aged more than Islamic Republic Of, 17Sydney Children’s Hospital, Randwick NSW, 18 40-50 years, first line treatment consists in the association of Australia, Our Lady’s Children’s Hospital, Dublin, Ireland anti-thymocyte globuline (ATG) and ciclosporine. The associa- tion of horse ATG (ATGAM) in combination with ciclosporine Introduction: Diskeratosis Congenita (DKC) is a rare telomere represents the reference immunosuppressive platform in this disease characterized by mucocutaneous features, liver an situation. Since September 2011, more than 400 patients have lung diseases and bone marrow failure usually diagnosed in been treated with this association in France on a temporary infancy. Haematopoietic Stem cell Trasplantation (HSCT) is the use based program because of AA (severe, moderate or only definitive treatment to restore hematopoiesis. Historically, refractory). Long-term outcomes including responses rates on HSCT was associated with significant morbidity and mortality, this large number of patients will be presented during the but extensive reports on its outcome are lacking. EBMT data meeting. base is a unique opportunity to collect data on the outcome Disclosure of Interest: None declared. and risk factors of HSCT in this disease. Patients and Methods: All patients registered in the EBMT data base and affected with DKC were considered eligible to the study. Data regarding type of HSCT, characteristic of Paediatrics Diseases donors, source of cells, incidence of acute and chronic GvHD and outcome were extracted from the Promise Data Base ‘‘MED B form’’. Results: A total of 84 DKC patients who underwent HSCT from WP011 1979 to 2013 entered the study. Females were 23% of the Influence of serotherapy in CD3/CD19 depleted cohort. Median age at diagnosis of DKC was 5.7 years (0-33y), haploidentical stem cell grafts after reduced intensity while median age at HSCT was 12.3 years (range 0.56-41y). conditioning Median time from diagnosis to HSCT was 22 months (0.62-278 P. Bader1,*, A. Jarisch1, J. Soerensen1, H. Kreyenberg1, T. Krenn2, mo). The cell source was bone marrow (BM) in 60%, peripheral M. Du¨rken3, J. Faber4, S. Huenecke1, C. Brehm1, M. Bremm1, blood (PB) in 26% and cord blood (CB) 14%. Thirthy-three E. Rettinger1, E. Ullrich1, M. Merker1, E. Salzmann-Manrique1, percent of patients were engrafted from a matched related and A. Willasch1, T. Klingebiel1 50% from an matched unrelated donor. Fourteen percent were 1Children and Adolescent Medicine, Goethe University, Frankfurt, mismatched related and unrelated HSCT. Engraftment was 2Children and Adolescent Medicine, Children Hospital Homburg, documented in 88% of subjects: 6.5% had primary graft failure Homburg, 3Children and Adolescent Medicine, University and 4% lost the engraftment. Overall 25 patients (33%) died, Children’s Hospital, Mannheim, 4Hematology Oncology, and 59 were alive (67%). Causes of death were: rejection graft/ University Children’s Hospital, Mainz, Germany loss of graft 28%, infections 24%, non-infectious interstitial pneumonia 16%, multi-organ failure 12%, secondary malig- Introduction: Transplantations using alternative donor nancies 12%, GvDH in 8%. Lung injury was present in more sources such as unrelated cord blood or haploidentical stem than one third of the subjects who died. Transplant related cells are of increasing importance. However, despite trans- mortality of the whole cohort was 18%. Acute GVDH occurred planting ‘‘megadoses’’ (410x106/kg BW) of stem cells and in 67% of the cohort, mainly of grade I and II (31%) and grade aggressive, immune suppressive conditioning, primary graft III in 6% of the cohort. No grade IV aGvHD has been rejection, delayed immune recovery and as a consequence an documented. The 5-year OS and EFS (death, relapse, second increased risk of transplant related mortality (TRM) remained tumours, primary and secondary graft failure being the events) major obstacles for the success of this treatment approach. To were 63% and 51% respectively with no plateau shown by the reduce TRM, we have started at Frankfurt University Children’s EFS curve. Over a follow up of 12 months, OS was 87% for Hospital a prospective trial using a reduced intensity patients transplanted at age 0-12 years and 75% for those at preparative regimen consisting of fludarabine, melphalan, age 412 years (P ¼ 0.23). Interval between the diagnosis and thiotepa and OKT3 graft manipulation with CD3/CD19 transplant (424 months and o24 months) did not signifi- depleted peripheral stem cells. cantly impact on the 5 years-OS which was assessed Patients and transplant procedure: Until December 31, 2010 respectevely at 72% and 53% (P ¼ 0.14). Source of cells did we have had included 73 patients (ALL n ¼ 16; AML n ¼ 16; not seem to impact on either OS or EFS although a precocious CML n ¼ 2; MDS n ¼ 4; solid tumors n ¼ 23, non-malignant fall in the curve was observed for CB and PB rather than for BM. diseases n ¼ 73). In these patients we observe a TRM rate of Conclusions: HSCT may restore hematopoiesis in DKC but its 11% and a rejection rate of only 6%. pEFS in patients with outcome looks influenced by the intrinsic morbility risk of this acute leukemia in remission was 74% as of January 31st, 2010.

S100 From beginning of 2011 OKT3 was taken from the market and Engraftment and incidence and severity of acute GVHD were was no longer available. Using the same conditioning regimen, similar and non- relapse mortality (NRM) was 7% vs 13% OKT3 was substituted by ATG with a total dose of 3x20 mg/kg. (P ¼ 0.10). Other significant influencing factors were: interval In the following 10 patients (ALL n ¼ 1, AML ¼ 1, solid tumors between diagnosis and transplantation below or beyond 208 n ¼ 4, and non-malignant diseases n ¼ 4) the TRM rate and days (NRM 6% vs 16%, P ¼ 0.015), donor sibling vs other (RI rejection rate increased to 30% each. In vivo analysis of ATG 35% vs 23%, P ¼ 0.01, NRM 5% vs 16%, P ¼ 0.001) and in vivo T serum levels revealed significant and unpredictable intra cell depletion (TCD) vs no TCD (RI 35% vs. 19%, P ¼ 0.003; NRM patient variability. Some patients did not develop therapeutic 20% vs 4%, P ¼ 0.0001). In the cox model, conditioning type doses of ATG and rejected their grafts; others showed high (Bu/CY/VP vs other), age, year of transplantation, interval from levels of persisting ATG and did not recover properly with their diagnosis to transplant, donor type, stem cell source and T-cell function. in vivo TCD were evaluated. For LFS only BU/CY/VP was As a consequence we switched from ATG to low dose associated with better outcome (P ¼ 0.004, HR.52), RI was Alemtuzumab 0.5 mg/kg and added three days chemotherapy lower after Bu/Cy/VP (HR.54, P ¼ 0.02), NRM was higher in pts with clofarabine, cyclophosphamide and etoposide in front of older than 4,6 years (P ¼ 0.02, HR 2,48) and after TCD HSCT the conditioning regimen. After this adoption, all 9 of the (P ¼ 0.01, HR 9,13) and OS was best after Bu/Cy/VP (P ¼ 0.03, following patients showed a proper and sustained engraft- HR 0.57). For pts in CR2, no significant influence of ment and adequate immune reconstitution, none of these conditioning regimen was observed. Here, a significant patients died due to TRM. influence for leukemia free survival was detected for the Today we have treated altogether 46 patients with leukemia interval between diagnosis to transplantation, non- relapse (ALL n ¼ 22; AML n ¼ 22, and CML n ¼ 2). In total cohort of mortality was higher for patients older than 7,7 years and for patients rejection rate was 4% and cumulative incidence (CI) of patients who received a non-sibling-HSCT. TRM at 2 years was 14% for all patients and 11% for patients in We conclude that omission of TBI is feasible for children who remission. undergo first allogeneic HSCT in first or second complete The pEFS of patients in remission (n ¼ 32) was 60% (median remission. The combination of busulfan, cyclophosphamide follow up 3 years) where as only 3/14 patients (median follow and etoposide resulted in better LFS and OS with less NRM up 3 months) who entered transplant without a prior and RI for children who received bone marrow or peripheral remission are currently alive without MRD. blood stem cells in CR1. These observations should be the Conclusion: Transplants with CD3/19 depleted stem cell grafts basis for prospective trials in homogenous patient groups. using mismatched donors is feasible after reduced intensity Disclosure of Interest: C. Peters Funding from: Medac; conditioning regimens but the outcome is depending on Fresenius, AOP Orphan, P. Sedlacek: None declared, J.-H. Dalle: serotherapy for the prevention of rejection. None declared, P. Bader: None declared. Disclosure of Interest: None declared. WP013 WP012 SCT in pediatric AML: Does the type of conditioning Non-TBI-containing Conditioing in Children with Acute regimen matter? Analysis on behalf of the Pediatric Lymphoblastic Leukemia. An analysis on behalf of the Disease Working Party of the EBMT Paediatric Diseases Working Party G. Lucchini1,*, M. Labopin2, A. Dalissier2, J. H. Dalle3, J. Cornish4, C. Peters1,*, P. Sedlacek 2, J.-H. Dalle3, P. Bader4 on behalf of S. Samarasinghe1, M. Zecca5, B. Gibson6, F. Locatelli7, paediatric Diseases Working Party Y. Bertrand8, F. Abdel-Rahaman9, G. Socie’10, P. Ljungman11, 1St. Anna Children’s Hospital, Vienna, Austria, 2University Motol, J. H. Veelken12, P. Sedlacek13, R.-M. Hamladji14, R. Hough15, Prague, Czech Republic, 3University Debre, Paris, France, 4Uni- H. Sengeloev16, B. Afanasyev17, C. Peters18, P. Bader19, versity Clinic Frankfurt, Frankfurt, Germany P. Veys1on behalf of PDWP 1Great Ormond Street Hospital, London, United Kingdom, Most children with acute lymphoblastic leukemia (ALL) with 2Universite’ Pierre et Marie Curie, 3Hoˆpital Robert Debre, Paris, indication for allogeneic hematopoietic stem cell transplanta- France, 4Royal Hospital for Children, Bristol, United Kingdom, tion (HSCT) receive myeloablative conditioning with a total 5Ospedale San Matteo, Pavia, Italy, 6Royal Hospital for Sick body irradiation (TBI)-containing regimen. To investigate the Children, Glasgow, United Kingdom, 7IRCCS Bambino Gesu’ outcomes of patients (pts) who did not undergo TBI, we Children Hospital, Rome, Italy, 8IHOP, Lyon, France, 9King Hussein performed a retrospective registry based study on children Cancer Centre, Amman, Jordan, 10Hoˆpital St. Louis, Paris, France, below 18 years who received a myeloablative chemo- 11Karolinska University Hospital, Stockholm, Sweden, 12Leiden conditioning for a first allogeneic HSCT from different donors University Hospital, Leiden, Netherlands, 13University Hospital between 2000 and 2012. In total, 732 pts were included: 313 Motol, Prague, Czech Republic, 14Centre Pierre et Marie Curie, pts who received bone marrow (BM) or peripheral blood stem Alger, Algeria, 15University College Hospital, London, United cells (PBSC) in 1st CR, 247 pts with BM/PBSC transplantation in Kingdom, 16Rigshospitalet, Copenhagen, Denmark, 17Saint CR2, 85 pts and 52 pts who received umbilical cord blood (CB) Petersburg State Medical Pavlov University, Ratsa Gorbacheva in 1st or 2nd CR, respectively. The most commonly applied Memorial Children`s Institute, St. Petersburg, Russian Federation, myeloablative chemo-combinations were: Busulfan (Bu)/Cyclo- 18St. Anna Kinderspital, Vienna, Austria, 19Universita¨tsklinikum phosphamide (Cy) (n ¼ 202), Bu/Cy/Etoposide (VP) (n ¼ 189), Frankfurt, Goethe-Universita¨t, Frankfurt am Main, Germany Bu/Cy/Melphalan (Mel) (n ¼ 93), Bu/AraC/Mel (n ¼ 80), Bu/ Fludarabine (Flu)/Thiotepa (Thio) (n ¼ 62), Bu/Cy/Thio (n ¼ 53, Introduction: Haematopoietic Stem Cell Transplantion (SCT) Bu/Cy/Thio (n ¼ 53), and Bu/Flu (n ¼ 53). has been the cornerstone of treatment in paediatric high risk Median follow up was 26 months (1-156). we compared Bu/Cy/ and relapsed acute myeloid leukaemia (AML). The optimal VP vs the other chemo-conditioning regimens. The Bu/Cy/VP conditioning regimen, and in particular the use of total body cohort had a longer follow up (med 37 vs. 20 months, irradiation (TBI) or chemotherapy-only conditioning regimens P ¼ 0.002), pts were younger (med 3,6 vs. 6,5 years, P ¼ 0.003) is still under debate. The aim of the present study was to and the median year of transplant was earlier (med 2009 vs. compare outcomes of pediatric AML patients undergoing SCT 2010, P ¼ 0.03). Donor type, CMV match, gender match, stem using three different conditioning regimens: TBI and cyclopho- cell were comparable. In univariate analysis, conditioning with sphamide (TBI-Cy), Busulfan and Cyclophosphamide (BuCy) or Bu/Cy/VP was better than all other combinations for pts who Busulfan, Cyclophosphamide and Melphalan (BuCyMel). were transplanted in first complete remission: relapse Pts and methods: In this retrospective study, registry data incidence (RI) 21% vs 32% (P ¼ 0.05), leukemia-free survival available for ptso18 yrs age undergoing matched allogeneic (LFS) 72 vs 54% (P ¼ 0.004), overall survival (OS) 79 vs 68% SCT for AML between 1997 and 2010 in 204 EBMT Centres were (P ¼ 0.03) and chronic GVHD (cGVHD) 9% vs 19% (P ¼ 0.014). analysed. Remission status, patient demographics, type of

S101 donor, stem cell source, use of T cell depletion, year of SCT, We present here a survey conducted by the Paediatric WP of interval from diagnosis to SCT were included in the Cox the EBMT, we aim to analyze and compare the different regression model to evaluate their impact on patient’s outcome. fertility preservation practices for children and adolescent Results: Data were available for 1381 pts. At SCT, 862 children across the EBMT centers and to identify hence the unmet were in 1CR, 375 in Z2CR and 144 had active disease. 833 pts needs in the field. In a second step, based on collected data, received SCT from a matched sibling and 548 from a matched we aim to promote fertility preservation guidelines for future unrelated donor. For 995 pts, bone marrow was used as stem standardization. cell source, and 386 pts received peripheral stem cells. 335 pts Materials (or patients) and methods: The survey was received TBI-Cy, 718 BuCy and 328 BuCyMel as preparatory initiated in September 2014. 188 paediatric centers reporting regimen. In 485 pts in vivo/vitro T cell depletion was to the EBMT were asked to fill-out a question form with 24 employed. Median follow up was 63 months. Non-engraft- questions related to fertility preservation strategies. ment was less common in the TBI-Cy group (0.3% TBI-Cy vs The questions inquired about availability of a fertility 2.6% BuCy 2.2% BuCyMel, Po0.05). No rejection related preservation program and its options, number of the patients deaths were reported in the TBI-Cy group, whereas 2 graft included in the program, payers and suggestions for failure-related deaths were documented in the non-radiation improvement. exposed groups. Among patients in CR1, those receiving Results: Until November 30th, 17 centers from 7 countries BuCyMel showed a statistically significant lower relapse replied. Information on 413 patients, who received an incidence (RI) at 5 years (18.5% vs 31.5% in BuCy vs 30.1% in allogeneic stem cell transplantation in 2013 was reported. TBI-Cy, Po0.05), higher overall survival (OS) (76.6% vs 65.5% vs The results showed that. 130/413 (31%) patients received a 63.1%, Po0.05) and leukemia free survival (LFS) (72.8% vs fertility preservation counselling and in 83 (20%) patients a 59.3% vs 60.0%, Po0.05), with a comparable non relapse fertility preservation procedure was performed. mortality (NRM) (8.7% vs 9.3% vs 9.9%, P ¼ 0.89). For pts Half of all centers reported to have a standard operating Z2CR, the conditioning regimen did not impact significantly procedure. The majority (8/9) of the centers perform the on the outcome, and among patients undergoing SCT in non- counselling at the beginning of treatment. Counselling team remission, a trend was observed for reduced 5-yrs RI when was multidisciplinary constituted in most of the centers (94%) comparing BuCyMel with TBI-Cy (46.5% vs 61.8%, P ¼ 0.05), by haemotologist, gynecologists and /or reproductive medi- but this did not translate into a better 5-yrs OS (29.8% vs cine specialists. Advisory concept involving more than one 26.1%, P ¼ 0.82) probably because of increased NRM (29.5% in specialist was largely preferred. The topic fertility preservation BuCyMel vs 11.8% in TBICy, P ¼ 0.05). Acute GVHD grade II-IV itself was assessed as relevant from all participants. Better was similar among TBI-Cy and BuCy conditioned patients education and financial funding emerged as pivotal factors to (32.2% vs 29.9%, P ¼ 0.5), but higher in patients receiving support the program. BuCyMel (42.1%, P ¼ 0.01); chronic GvHD was similar between Conclusion: This preliminary data showed a great interest on the 3 groups (27.2% vs 24% vs 26.7% P ¼ 0.59). In the Cox the topic within the EBMT community, however the number of regression model including all patients, BuCyMel had a fertility preservation counselling performed involved less than significant impact on RI (HR 0.65, 95%CI 0.48-0.89, one third of the patients, and the low number of fertility Po0.05),higher age at SCT raised the risk for NRM, and preservation procedures emphasize the need of education and remission status and time from diagnosis to SCT were promotion in the field. This is an ongoing survey, data collection significant factors for LFS, RI, NRM and OS. will continue until 1th March 2015, an extended up- dated Conclusion: Among paediatric patients receiving SCT for AML analysis will be presented at the 41th Annual Meeting of EBMT in CR1 the use of BuCyMel conditioning proved superior to Disclosure of Interest: None declared. TBI-Cy and BuCy in reducing RI and improving LFS. Moreover, it did not increase NRM nor cGVHD, accounting for an overall higher OS. We speculate that this result may be linked to a WP015 higher rate GvHD and increased GVL effect. What we always wanted to know about paediatric Disclosure of Interest: None declared. GVHD-prohylaxis and treatment: a survey by the Paediatric Diseases Working Party (PDWP) of the European Society for Blood and Marrow Transplantation (EBMT) WP014 A. Lawitschka1,*, A. Balduzzi2, C. Diaz De Heredia3, Fertility preservation in paediatric and adolescent patients J. Wachowiak4, J.-H. Dalle5, P. Bader6, C. Peters1 on behalf of undergoing HSCT- a cross-sectional survey of the Pediatric Diseases Working Party Paediatric WP of the EBMT 1SCT unit, St.Anna Children’s Hospital, Vienna, Austria, 2HSCT T. Diesch-Furlanetto1,*on behalf of Paediatric WPP, A. Rovoˆ2, pediatric Unit, San Gerardo Hospital, Monza, Italy, 34Servicio de N. von der Weid3, M. Faraci4on behalf of Paediatric WPP, Hematologia y Oncologia Pedia´trica, Hospital Vall d’Hebron, M. Pillon5, P. Bader6on behalf of Paediatric WPP Barcelona, Spain, 4Dep. of Pediatric Oncology, University of 1Paediatric Haematology/Oncology, University CHirlen’s Hospital Medical Sciences, poznan, Poland, 5Pediatric Immuno-Hematol- of basel, Basel, 2Deaprtment of Heamatology, University Hospital ogy Unit, Robert Debre´ Hospital, Paris, France, 6Division for Stem of Bern, Bern, 3Departemnt of Peadiatric Haematology/Oncology, Cell Transplantation, University Children’s Hospital, Frankfurt/ University Children’s Hospital of Basel, Basel, Switzerland, Main, Germany 4Haematology/Oncology, Gaslini Research Institute G. Gaslini, Genova, 5Deoartment of Paediatric Haematology/Oncology, More information on routine transplant procedures like GVHD Hospital of Padua, Padua, Italy, 6Divison of Stem Cell prophylaxis and treatment should make it possible to create Transplanation and Immunology, Hospital of Children and standards, to better understand the impact of differences on Adolescent of Frankfurt, Frankfurt, Germany varying outcome data and to subsequently perform prospec- tive clinical trials. Therefore the PDWP performed a survey Introduction: With the improvement of cancer survival rates among EBMT centres performing allogeneic transplantations for paediatric and young adult patients, considerations in children and adolescents about their strategies in prevent- regarding long-term effects of therapy have become more ing and treating GVHD. The questionnaire covered details important. It is known that cancer therapy may be gonado- about GVHD prophylaxis in myeloablative and reduced toxic leading to pubertal development impairment and intensity conditioning and the possible influence of donor infertility. Infertility may result in a substantial restriction in type, stem cell source and potential risk factors. Of further quality of life. In the last years many fertility preservation interest were treatment components of acute and chronic guidelines for cancer patients have been published. Despite GVHD, time points of evaluation and definitions of response. these recommendations options for fertility preservation are Responses from 52 centres (26%) from 22 countries were only discussed in about 40% of all eligible patients. received and analyzed.

S102 This survey shows a distinct heterogeneity both in prophylaxis strategies and methods. Their final goal is to improve the and treatment of acute and chronic GVHD despite superficially outcome of transplantations. The number of published guide- similar protocols and standardization of at least some central linesandrecommendationsissubstantialbuttheirimpactand procedures would be needed. effect on transplantation strategies in individual centres has Disclosure of Interest: None declared. never been investigated. A group of experts from the EBMT and the European LeukemiaNet published recently a consensus paper on recommendations for a standard practice in the prophylaxis and treatment of GVHD (‘‘Prophylaxis and treatment Complications and Quality of Life of graft-versus-host disease: EBMT–ELN working group recom- mendations for a standardized practice’’ by T Ruutu, A Gratwohl, TdeWitteet al, Bone Marrow Transplantation 49 (2): 168-173, 2014). According to the JACIE policies for change control, the WP016 decision has been made to carry out a follow-up survey. Its goal Nurse-led screening of long-term transplant complications is to describe the impact of these recommendations.Materials D. Greenfield1,* and methods: A questionnaire containing 14 questions has been 1North Trent BMT Programme, Sheffield Teaching Hospitals NHS distributed to all EBMT centres performing allogeneic transplan- Trust, Sheffield, United Kingdom tations. The questions deal with the awareness of the centres about the recommendations and the sources of information; Introduction: HCT survivors are at risk for developing late they ask whether the recommendations have been regarded as complications secondary to pre-, peri-, and post-transplanta- useful and whether they have led to changes in transplantation tion exposures and risk factors. Updated recommendations for strategies or methods. The survey also asks about the willingness late effects screening for survivors of autologous and of the centres to use the recommended standard protocol as a allogeneic HCT were published in 20121. The aim of this control arm in their own or EBMT studies to develop study was to assess the clinical efficacy of a screening clinic to transplantation strategies. identify late complications of HCT. Results: The survey is ongoing. Materials (or patients) and methods: Our centre implemented Conclusions: The survey will give information about how the internationally agreed guidelines in 2013 using a locally centres experience this kind of recommendations or guide- developed Standardised Operating Policy (SOP) through a lines, how useful they are thought to be, and how much they nurse-led late effects screening clinic. 59 consecutive patients in practice affect the strategies and methods of the centres. who attended the screening clinic for the first time during 1st This information could contribute to the planning of future Sept 2013 to 31st Aug 2014 were included in the audit. Data EBMT recommendations and guidelines. was extracted from the clinic letter annotated from the Disclosure of Interest: None declared. consultation and from results of the requested investigations as per the SOP. Presence or absence of each variable and investigation was coded and current results and actions were WP018 recorded in a spreadsheet. Audit approval confirmation was Development of an eTool to support decision making given by the Clinical Effectiveness Unit of our hospital trust. in the diagnosis and treatment of GVHD H. Schoemans1,* Results: 30 female and 29 male HCT survivors with a mean 1 age of 49 years and a mean 6 years post-transplant attended Dept. of Hematology, University Hospital Gasthuisberg, Leuven, the nurse-led late effects clinic as new patients in the time Belgium period. 49/65 were allogeneic HCTs. 54 had one transplant procedure, 4 had 2 and one had 3 procedures.13 patients The 2005 NIH criteria for graft versus host disease (GVHD) received TBI radiotherapy. 43/59 primary indications for HCT diagnosis and treatment provide an opportunity for standar- were lymphoid diseases, 12/59 were myeloid diseases with dization of diagnosis and treatment of GVHD, yet their 3/59 were solid tumour and 1/59 had an autoimmune disease. complexity is often considered by clinicians as time consum- 134 late complications were identified in 59 patients with 114 ing, limiting their successful implementation and scalability in requiring further action or referral, mean complication per daily clinical practice. Transplant physicians might be therefore patient ¼ 2. The most frequent late complications were pain helped by a decision support system developed as an eTool. 18/59 (31%), sleep disturbance 11/59(19%), fatigue 14/59(24%) An eTool is defined as ‘‘a computer or web based application and sexual function concerns 14/59(24%). intended to make a task easier’’. An eTool can thus be Conclusion: To our knowledge this is the first time new integrated in electronic patient records or Apps and support international late effect screening guidelines have been audited. the quality of care in stem cell transplant programs. We This new nurse-led screening clinics demonstrates clinical designed an eTool to guide and support clinical decision efficacy in identifying late complications using holistic screen- making in view of acute and chronic GVHD diagnosis and ing. This will inevitably result in earlier detection of problems scoring based on the 2005 NIH criteria. More specifically, the and may prevent and/or reduce morbidity therefore playing a eTool is developed as a screen which lists the various central role in optimising quality of life for HCT survivors. Future symptoms over different organ systems related to GVHD. research should look at complications and their link to certain Clinicians score each symptom (as present: yes/no) and an treatments and whether these complications can be reduced algorithm based diagnosis and score is generated subse- using different transplantation exposures. quently. For chronic and overlap GVHD, four levels of Disclosure of Interest: None declared. symptoms (none, mild, moderate or severe) of eight organs reflecting the 2005 NIH criteria are scored (skin, mouth, eyes, gastro-intestinal, liver, lungs, muscles and genitals) resulting in WP017 an overall mild, moderate or severe score. For acute GVHD, Follow-up Survey of the EBMT-ELN Working Group four levels of gravity of symptoms over three organ systems Recommendations on the Prophylaxis and Treatment (skin, gastro-intestinal and liver) are scored yielding of GVHD a Gluckberg score (ranging from I-IV) and IBMTR score T. Ruutu1,* (ranging from A to D). Both sub-modules (diagnosis and 1Stem Cell Tranplant Unit, HUCH Comprehensive Cancer Center, scoring) of the eTool require about 30-60 sec to complete. Our Helsinki, Finland eTool as decision making support system for diagnosis and treatment of GVHD has the potential to enhance quality of Introduction: The working parties and study groups of the EBMT care in stem cell transplant centers as well as in research in have a long tradition to produce guidelines and recommenda- view of more accurate and reliable scoring of GVHD. tions for standard practice in order to develop transplantation Admittedly, further testing is indicated, yet first experiences

S103 at the University Hospitals of Leuven where the tool has been infections and excessive inflammation from early life. integrated in the electronic medical record are very positive. Allogeneic haemopoietic stem-cell transplantation (HSCT) Disclosure of Interest: None declared. is curative but can be complicated by graft-failure, graft-versus-host disease (GVHD), infection and transplant- WP019 related mortality. Reduced-intensity conditioning regimens T-control: GVHD immunotherapy under the EU 7th have been used with the aim of reducing organ toxicity whilst Framework Programme maintaining good myeloid engraftment. We report the use of Treosulfan, an immuno-suppressive and myeloablative A. Madrigal1,* 1 alkylating agent, as part of conditioning for HSCT in children Anthony Nolan, Royal free London NHS Foundation Trust, with CGD. London, United Kingdom Materials and methods: Retrospective study done at 14 centres in eight countries worldwide. Centres submitted data Patients with high-risk hematological tumours can be cured by from their paediatric patients diagnosed with CGD who allogeneic hematopoietic stem cell transplantation (HSCT). underwent HSCT using a Treosulfan based conditioning However, the main causes of failure of HSCT are infections, regimen. The following data were collected: risk features prior tumour relapse and over-shooting immune responses of the to transplant, additional conditioning agents to Treosulfan, donor T cells to healthy cells and tissues of the patient or graft- donor type and stem cell source, toxicity, engraftment, GVHD, versus host disease (GvHD). Therefore, this treatment is still chimerism, viral reactivation, transplant complications, length associated with a high morbidity and mortality, as well as a of follow up and outcome. high economic burden. Our previous EU FP6 project, Results: 67 paediatric patients (median age 106 months; ALLOSTEM, resulted in a number of achievements, including IQR 46–232) with CGD were transplanted from August a first in man clinical trial that used a highly innovative novel 2006 to October 2014. 56 patients (84%) had high-risk features cell selection strategy (Streptamer technology) for the gen- (ie, intractable infections and autoinflammation). 12 eration of non-ATMP (advanced therapy medicinal product) HLA-matched related-donor, 54 10/10 or 9/10 HLA-matched monovirus specific T cell products. Continuing from ALLOS- unrelated-donor and 1 TCR alpha beta/CD19 depleted TEM, we now aim to develop two novel Streptamer-based parental haplo transplants were performed. Half of the clinical cell selection processes and its corresponding cell patients received bone marrow half peripheral blood stem products. A multispecific T cell product targeting several cells. The regimen most commonly used was Treosulfan, viruses and tumours as well as a primary regulatory T cell Fludarabine þ /- serotherapy in 44 patients (66%). No product targeting GvHD will be developed to market maturity. patients experienced major complications related to These two cell products will improve the outcome of conditioning such as veno-occlusive disease (VOD). allogeneic HSCT. A significant improvement in the outcome Median time to engraftment was 17 days (IQR 14–35) for and this coupled with a significant reduction of the costs for a neutrophils and 16 days (IQR 13–50) for platelets. 28 patients large number of patients in Europe will further broaden the (41%) had viral reactivations including CMV (n ¼ 20), application in other forms of cancer of this curative treatment. EBV (n ¼ 11), adenovirus (n ¼ 7) and HHV6 (n ¼ 4). The In order to achieve this goal we assembled a consortium led cumulative incidence of acute GVHD grade III–IV was 12% (8 by the SME Stage cell therapeutics GmbH together with patients), 9 patients had chronic GVHD 13%. 3 of these renowned clinical scientists in the field of HSCT (all key players patients died and in 4 GVHD resolved. When split chimerism in ALLOSTEM). Additional information on T-Control available at was available, and excluding those who had second http://www.t-control.info/. procedures, stable (Z95%) myeloid donor chimerism was Disclosure of Interest: None declared. documented in 44 (91,6%) surviving patients. At median follow-up of 32 months (IQR 13–100) overall survival was 91% (61 of 67) and EFS was 80% (54 of 67). Transplant related mortality affected 2 patients. Graft-failure occurred in Inborn Errors 7% (5 of 67) of patients. Conclusion: We demonstrate excellent survival with low transplant related mortality and in particular no cases of VOD. Myeloid chimerism is also excellent. Longterm WP020 follow up is required to ascertain effects particularly on Treosulfan based regimen for paediatric CGD patients. gonadal function. Further prospective trials using precisely Multicentre experience defined protocols with pharmacokinetic monitoring compar- B. Morillo-Gutierrez1,*, K. Rao2, Z. Allwood2, L. Burroughs3, ing treosulfan with low dose Busulfan and Fludarabine are A.-M. Ewins4, C. Fraser5, K. Kalwak6, I. Meyts7,I.Mu¨ller8, warranted. A. Schulz9, P. Sedla´cˇek10, B. Strahm11, J. Wachowiak 12, References:Gu¨ngo¨rTet al. Reduced-intensity conditioning I. Zaidman13, A. Gennery14, K.-W. Sykora15, M. Slatter1,14 and HLA-matched haemopoietic stem-cell trans- 1Department of Paediatric Immunology, Great North Children´s plantation in patients with chronic granulomatous disease: Hospital, Newcastle Upon Tyne, 2Paediatric Bone Marrow Trans- a prospective multicentre study. The Lancet. 2014;383 plant, Great Ormond Street Hospital, London, United Kingdom, (9915):436-48. 3Paediatric Bone Marrow Transplantation, University of Washing- Greystoke B et al. Treosulfan-containing regimens achieve ton School of Medicine, Seattle, United States, 4Paediatric Bone high rates of engraftment associated with low transplant Marrow Transplantation Schiehallion Unit, Royal Hospital for Sick morbidity and mortality in children with non-malignant Children, Glasgow, United Kingdom, 5Royal Childrens Hospital, disease and significant co-morbidities. Br J Haematol. Brisbane, Australia, 6Wroclaw Medical University, Wroclaw, Poland, 2008;142(2):257-62. 7UK Leuven, Leuven, Belgium, 8University Medical Center Hamburg- Disclosure of Interest: None declared. Eppendorf, 9Universita¨tsklinik fu¨r Kinder- und Jugendmedizin, Hamburg, Germany, 10Teaching Hospital Motol, Prague, Czech Republic, 11Freiburg University, Freiburg, Germany, 12University of Medical Sciences, Poznan, Poland, 13Rambam Hospital, Haifa, Israel, 14Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom, 15Hannover Medical School, Hannover, Germany

Introduction: Chronic granulomatous disease (CGD) is a primary immunodeficiency that predisposes to severe

S104 WP021 basis of SCID has markedly increased. Parallel developments in Hematopoietic stem cell transplantation between 1968 HSCT supportive care and HLA typing technology have and 2013 for Severe Combined Immune Deficiency (SCID) contributed to improved outcome of HSCT. The objective of below age two: an update by the European Registry this study is to analyse by decade the outcome of SCID (SCETIDE) patients transplanted o2 years of age from European centres, A. Lankester1on behalf of EBMT IEWP, R. Bredius1,*, N. Mahlaoui2, between 1968 and 2013. V. Courteille2, J. Provot2, M. Honig3, A. Schulz3, M. Slatter4, Materials (or patients) and methods: The SCETIDE online B. Gaspar5, P. Veys6, D. Moshous7, B. Neven7, S. Blanche7, registry system (www.scetide.org) and database was used to M. Cavazzana-Calvo8, A. Fischer7, A. Gennery4 on behalf of on collect and analyse reported patients from 80 European behalf of EBMT IEWP centres. 1BMT Unit, Leiden University Centre, Leiden, Netherlands, Results: As of December 2014, 1354 patients transplanted 2CEREDIH, Necker Hospital, Paris, France, 3Pediatrics and below the age of two were reported between 1968-2013 Adolescent Medicine, University Hospital Ulm, Ulm, Germany, by 58 centres. Within this cohort, 89% and 11% of patients 4Paediatric Immunology Dept, Great North Children’s were transplanted for SCID and Omenn syndrome, respectively. Hospital, Newcastle upon Tyne, 5Immunology, 6BMT Unit, GOSH, The majority are male (64%). Donor types included HLA London, United Kingdom, 7UIHR, 8Biotherapie, Necker Hospital, matched siblings in 18%, (mismatched) parents in 42% and Paris, France matched unrelated donors in 11% of the cases. Stem cell source was BM in 66%, PBSC in 21% and CB in 11% of HSCT. Overall Introduction: Hematopoietic stem cell transplantation (HSCT) survival of the entire cohort is 67% (figure). Survival has is curative for severe combined immunodeficiency (SCID). To improved over the last decades and identical donors have improve knowledge on HSCT outcome and care for patients better overall survival rates (figure). Patients with active/ongoing with SCID the SCETIDE registry was created 30 years ago on infection have an inferior outcome (77% alive with vs 91% behalf of EBMT IEWP. In this time period, insight in the genetic without infections).

[WP021]

S105 Conclusion: Outcome in HSCT for SCID has significantly occurred in 29 ( þ -5)% (10% grade 3-4) at day 100 and improved during last four decades. Better outcome in chronic-GvHD at 1 year 23( þ -4)% (extensive 8.6%). Informa- unrelated donor HSCT, younger age at HSCT, better HLA tion on disease-specific characteristics is currently collected. typing, better conditioning regimes and supportive care have Associations between pre-CBT disease status and long-term contributed to this improved outcome. follow up data will be presented during the EBMT 2015 The SCETIDE database will allow us to analyse some disease- meeting. specific outcome parameters. In conclusion, we found an encouraging OS of 61% at The superior outcome in young patients without active 5-years (58% in ALD, 49% Krabbe, 76%MLD), with relatively infectionshas important implications for the scheduled intro- low rates of GvHD. Use of a mismatched donor duction of newborn screening for SCID. (41 HLA disparity) negatively impacts survival. Data on Disclosure of Interest: None declared. clinical characteristics and neurological function pre- and post CBT is of importance and will be analyzed in upcoming months. WP022 Disclosure of Interest: None declared. Outcomes Of Allogeneic Cord Blood Transplantation For Leukodystrophies; A Joint Study of Eurocord, Duke University Medical Center Cord blood committee of WP023 Cellular Therapy and Immunobiology and Inborn Errors Hematopoietic Stem Cell Transplantation For WP-EBMT Patients With Primary Immune Deficiencies In J. J. Boelens1,*, J. Hol1, A. Ruggeri2, K. Page3, E. Gluckman2, Europe: An Update By The European Registry A. Gennery4, V. Rocha2,5, J. Kurtzberg3on behalf of (SCETIDE) N. Mahlaoui1,*, R. Bredius2, A. Lankester3on behalf of EBMT IEWP, DUMC CB Committee of Cellular Therapy and Immunobiology 1 1 4 4 5 on behalf of EUROCORD, EBMT WP-IE, Duke University Medical V. Courteille , J. Provot , M. Honig , A. Schulz , M. Slatter , B. Gaspar6, P. Veys7, D. Moshous8, B. Neven8, S. Blanche8, Center Cord Blood Committee of Cellular Therapy and 8 5 Immunobiology A. Fischer , A. Gennery on behalf of on behalf of EBMT IEWP 1 2 1CEREDIH, Necker Hospital, Paris, France, 2BMT Unit, Leiden University Medical Center Utrecht, Utrecht, Netherlands, Euro- 3 cord, Paris, France, 3DUMC, Durham, United States, 4Great North University Center, BMT Unit, Leiden University Center, Leiden, 5 Netherlands, 4Pediatrics and Adolescent Medicine, University Children’s Hospital, Newcastle, Oxford University Hospitals NHS 5 Trust, Oxford, United Kingdom Hospital Ulm, Ulm, Germany, Paediatric Immunology Dept, Great North Children’s Hospital, Newcastle upon Tyne, 6Immunology, 7BMT Unit, GOSH, London, United Kingdom, Leukodystrophies (LD) are rare inborn errors of meta- 8 bolism (IEM) interfering with brain myelination and UIHR, Necker Hospital, Paris, France characterized by rapid neurological deterioration and death. Hematopoietic cell transplantation (HCT) can halt Introduction: Hematopoietic stem cell transplantation (HSCT) disease progression for selected leukodystrophies, is curative for primary immune deficiencies (PID), either severe including adrenoleukodystrophy (ALD), Krabbe disease combined immunodeficiency (SCID) or non-severe combined (globoid cell leukodystrophy) and metachromatic leukodystro- immunodeficiency (non-SCID). To improve knowledge on phy (MLD). Unrelated cord blood has the advantage of HSCT outcome and care for patients with PID the SCETIDE being rapidly available to treat patients with these rapidly registry was created 30 years ago on behalf of EBMT IEWP. In progressive diseases. This study aims to describe outcomes this time period, insight in the genetic basis of PID has of allogeneic cord blood transplantation (CBT) in patients markedly increased. Parallel developments in HSCT supportive with LD. care and HLA typing technology have contributed to All patients undergoing CBT for these selected LD improved outcome of HSCT. The objective of this study reported to Eurocord or transplanted at Duke University is to analyse by decade the outcome of SCID and non-SCID Medical Center (DUMC) between 1996 and 2013 were patients transplanted from European centres between 1968 included. CBT data were collected from the EUROCORD and and 2013. DUMC database. An additional questionnaire on disease- Materials (or patients) and methods: The SCETIDE specific clinical outcomes was optimized and sent to online registry system (www.scetide.org) and database participating centers. Kaplan-Meier estimates were used to was used to collect and analyse reported patients from 80 calculate overall survival (OS) and cumulative incidence centres in 25 European centres. methods for secondary outcomes, including neutrophil and Results: As of December 2014, 3490 patients trans- platelet engraftment, incidence of graft-versus-host disease planted below the age of two were reported between (GvHD) and disease-specific characteristics and functional 1968-2013 by 80 centres. Within this cohort, 38% and outcomes at most recent follow-up (which needs to be 62% of patients were transplanted for SCID and analyzed). non-SCID, respectively. Non-SCID are other T-cell deficiencies Two hundred twenty patients (91 ALD, 51 Krabbe, 78 MLD) (19%), hemophagocytic lymphohistiocytoses (17%), were available for analysis: 195 single CB, 24 double, 1 Wiskott-Aldrich syndrome (9%), phagocytic disorders (12%) unknown: median total nucleated cell (NC) dose at and other PIDs (9%). The majority are male (66%). collection was 7.9 NC/kg. A busulfan-based myelo- Donor types included HLA matched siblings in 21%, ablative regimen was the most frequently used: 184/220 (mismatched) parents in 25% and (matched) unrelated (84%). The median interval between diagnosis and donors in 19% of the cases. Stem cell source was BM in transplantation was 3.4 months and the median age at 67%, PBSC in 21% and CB in 10% of HSCT. Overall survival of transplant was 6.7 years (yrs), 0.5yrs and 3.5yrs, for ALD, the entire cohort is 69%. Krabbe and MLD, respectively. Cumulative incidences Conclusion: Outcome in HSCT for PIDs has significantly of day 60 neutrophil and day 180 platelet engraftment were improved during last four decades. Better outcome in 88% (±2%), and 78% (±6%), respectively. Median follow-up unrelated donor HSCT, younger age at HSCT, better HLA was 56 (range 3–211) months. OS at 5 years for the typing, better conditioning regimes and supportive care have whole group was 61% (±3%) and 58%, 49%, 67% for ALD, contributed to this improved outcome. The SCETIDE database Krabbe and MLD, respectively. Of the 82 patients who will allow us to analyse some disease-specific outcome died, 20 (25%) died of disease progression, 57 (69%) of parameters. transplantation-related mortality, 5 unknown. Higher OS Disclosure of Interest: None declared. was seen in patients who had no or 1 HLA mismatch (OS 71%), compared to patients who received a CBT with 2 HLA mismatches (OS 56%, p 0.01). Acute-GvHD (grade II-IV)

S106 [WP023]

Chronic Malignancies 13Medizinische Klinik u. Poliklinik V, University of Heidelberg, Heidelberg, 14Bone Marrow Transplantation Centre, University Hospital Eppendorf, Hamburg, Germany

WP024 Objectives: AlloHCT is an important treatment option for Risk factors for adverse outcome in patients with Chronic patients with very high risk CLL. Risk factors for poor outcome Lymphocytic Leukemia (CLL) undergoing Allogeneic after alloHCT have so far only been defined in small cohorts. Hematopoietic Cell Transplantation (alloHCT): With available treatment alternatives like the BTK-inhibitor, A Retrospective EBMT Analysis ibrutinib, or the PI3K-inhibitor, idelalisib, patient selection for J. Schetelig1,2,*, L. de Wreede3, C. Moreno4, N. Smedegaard HCT becomes increasingly important. Therefore, we aimed at Andersen5, M. van Gelder6, M. Machaczka7, M. Gramatzki8, the identification of risk factors for adverse outcome of P. Dreger9, A. Vitek10, M. Karas11, M. Michallet12, A. Henseler3, alloHCT in patients with CLL. M. Bornha¨user1, S. Scho¨nland13, N. Kro¨ger14on behalf of CLL Patients and Methods: Patients with CLL who received a first subcommittee, Chronic Malignancies Working Party on behalf of alloHCT from a HLA-identical sibling or unrelated donor between CLL subcommittee, Chronic Malignancies Working Party 2000 and 2011 and the quality of whose baseline and outcome 1Medical Department I, University Hospital of the Technical data have recently been improved in the EBMT—CLL data quality University Dresden & DKMS Clinical Trials Unit, Dresden, 2DKMS, initiative were analyzed. We fitted multivariate Cox regression German Bone Marrow Donor Center Germany, Tu¨bingen, models for OS and PFS and analyzed the cause-specific hazard Germany, 3Dept. Medical Statistics & Bioinformatics, Leiden ratios for the competing endpoints relapse and NRM. University Medical Center, Leiden, Netherlands, 4Hematologia, Results: 580 patients (427 males, 153 females) were included Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 5BMT Unit into the analysis. The median follow-up after HCT was 3.7 y Dept. of Hematology, Rigshospitalitet, Copenhagen, Denmark, (years) (range, 0 -12y). The median age was 55 y (range, 6University Medical Center Maastricht, Maastricht, Netherlands, 19-74y). The EBMT consensus criteria for alloHCT were met for 7Department of Hematology, Karolinska University Hospital, 85% of the patients based on the presence of a deletion 17p, Stockholm, Sweden, 8Div. Stem Cell Transplantation and purinanalogue-refractory disease or early relapse after inten- Immunotherapy, University Hospital Schleswig-Holstein, Kiel, sive chemo-immunotherapy. Altogether, 42% had refractory 9Medizinische Klinik u. Poliklinik V, University of Heidelberg, disease at the time of HCT, 24% had high risk disease defined Heidelberg, Germany, 10Department of Haematology, Institute of by re-treatment within 24 months, while 34% had clinically Hematology and Blood Transfusion, Prague, 11Dept. of Hematol- less aggressive disease. 27% had a deletion 17p, 22% a ogy/Oncology, Charles University Hospital, Pilsen, Czech Republic, deletion 11q, 33% had other abnormalities while in the 12He´matologie, Centre Hospitalier Lyon-Sud, Lyon, France, remaining patients no cytogenetic abnormalities were

S107 described. Disease status at HCT was CR in 11%, PR in 49% and Results: 41 patients (30 males, 11 females) from 10 transplant SD/PD in 40%. Only 22% of patients had a Karnofsky score of centres were registered for this study between June 2010 and 80% or lower at the time of HCT. 40% of the patients had an Sept 17, 2012. The median age was 59 years (range, 28 to 70 HLA-identical sibling as donor, 48% a matched unrelated years). 12 patients (29%) were transplanted in first remission. donor and only 12% a partially matched unrelated donor. The The median number of pre-treatments was 2 (range, 1 to 7) complete case analysis comprises 520 patients (90%). and included alemtuzumab in 31 patients (76%). The For the whole cohort of patients the 5-year OS and PFS were remission status at HCT was reported as partial remission in 47% and 37%. The cumulative incidences of relapse and NRM 31 (76%) and as complete remission in 10 patients (24%). were 28% and 36%, respectively. For OS, performance status and The median time between diagnosis and HCT was 35 months patient sex (females had longer survival) had a significant impact (mo) (range, 4 to 229 mo) and the median time between first (Po0.05) on OS, whereas remission status, age, and donor type treatment of CLL and HCT was 12 months (range, 2 to 227 mo). were borderline significant (0.05oPo0.1). For PFS, remission Myeloablative conditioning was administered in 3 (7%), status, performance status and patient sex had a significant fludarabine-based reduced-intensity conditioning in 25 (61%) impact (Po0.05) on PFS. Age and donor type had no significant and non-myeloablative conditioning, based on 2 Gray TBI, in impact on PFS. Remission status and patient sex (females had 13 patients (32%). Donors were HLA-identical siblings for 11 less relapse) had a significant impact (Po0.05) on the (27%), well-matched HLA-compatible unrelated donors for 25 cumulative incidence of relapse. Finally, poorer performance (61%) and partially matched unrelated donors for 5 patients status, higher age and unrelated donor had a significantly (12%). 13 patients received ATG. 15 patients experienced negative impact on NRM. A female to male gender constellation grade II to IV GVHD. At the time of writing, 23 were alive and was associated with a trend toward higher non-relapse mortality. 18 patients had died. 7 patients died subsequent to relapse Notably, neither cytogenetic subgroup nor chemo-sensitivity and 11 patients died without relapse. Causes of death were had an impact on OS, PFS, incidence of relapse or NRM. GVHD in 8, infection in 1 and other causes in 2 patients. Conclusion: In a large cohort of patients who were trans- Altogether, 10 patients have experienced relapse after HCT so planted across Europe we can confirm that neither chemo- far. The median observation time for living patients was 29 mo sensitivity nor cytogenetic subgroup have a significant impact (range, 3 to 41 mo). The probability of relapse-free survival and on outcome after alloHCT. Patient sex and performance status OS at 2 years was 54% (95% CI, 38% to 70%) and 70% (95% CI, have a significant impact on OS and PFS and remission status 56% to 84%). At 2 years the cumulative incidences of relapse at HCT also impacts on PFS. In contrast, performance status, and NRM were 21% (95% CI, 7% to 35%) and 25% (95% CI, age and donor type are risk factors NRM. 10% to 40%). Information on the course of MRD is available for Disclosure of Interest: None declared. 31 patients. 23 patients had at least one MRD-negative assessment after HCT. So far, relapse was observed in 5 out of WP025 these 23 patients. Among 17 patients who were alive and Clearance of Minimal Residual Disease (MRD) in patients relapse-free at last follow-up and had MRD assessments with 17p-CLL after Allogeneic HCT: Results of the available, 13 patients were MRD-negative. Non-interventional Study of EBMT & ERIC Conclusions: With the availability of less toxic first-line therapies, like ibrutinib and idelalisib, the data suggests that J. Schetelig1,2,*,J.Hoek3, S. Stilgenbauer4,M.Bornha¨user1, 5 6 7 4 8 alloHCT should be regarded as treatment option only for N. Smedegaard Andersen ,C.Fox,S.Lenhoff,D.Bunjes,L.Volin, patients with relapsed 17p-CLL and for patients with a low risk A. Shimoni9,W.Schroyens10,M.vanGelder11,A.vanBiezen3, 12 13 14 15 for transplant-related mortality. L. de Wreede ,T.DeWitte ,N.Kro¨ger ,P.Dreger Disclosure of Interest: None declared. 1Medical Department I, University Hospital of the Technical University Dresden & DKMS Clinical Trials Unit, Dresden, 2DKMS, German Bone Marrow Donor Center Germany, Tu¨bingen, WP026 Germany, 3EBMT Data Office Leiden, Leiden, Netherlands, 4Ulm Allogeneic Hematopoietic Stem Cell Transplantation for University Hospital, Ulm, Germany, 5Rigshospitalet University Multiple Myeloma: Evolution and Outcomes over More Hospital Copenhagen, Copenhagen, Denmark, 6Nottingham City Than Two Decades within EBMT Centers Hospital, Nottingham, United Kingdom, 7University Hospital M. Michallet1,*, M. Sobh1, S. Iacobelli2, A. Van Biezen3, P. Dreger4, Lund, Lund, Sweden, 8Helsinki University Central Hospital, E. Petersen5, M. Schaap6, G. Bandini7, L. Volin8, E. Meijer9, Helsinki, Finland, 9Chaim Sheba Medical Center, Tel-Hashomer, D. Niederwieser10, H. Einsele 11, D. Blaise12, R. Tabrizi13, Israel, 10Antwerp University Hospital, Antwerp, Belgium, L. Vincent14, J. Finke15, D. Bunjes16, J. Cornelissen17, G. Gahrton18, 11University Medical Center Maastricht, Maastricht, 12Dept. L. Garderet19, N. Kro¨ger20 on behalf of The EBMT Chronic Medical Statistics & Bioinformatics, Leiden University Medical Malignancies Working Party Center, Leiden, 13Radboud University Nijmegen Medical Center, 1Hematology, Centre Hospitalier Lyon Sud, Pierre Be´nite, France, Nijmegen, Netherlands, 14Bone Marrow Transplantation Centre, 2Centro Interdipartimentale di Biostatistica e Bioinformatica, Uni- University Hospital Eppendorf, Hamburg, 15Medizinische Klinik u. versita` Tor Vergata, Rome, Italy, 3EBMT Data Office, Leiden, Poliklinik V, University of Heidelberg, Heidelberg, Germany Netherlands, 4Hematology, University of Heidelberg, Heidelberg, Germany, 5Hematology, University Medical Centre, Utrecht, 6Hema- Introduction: 17p-/TP53-mutated CLL (17p- CLL) represents tology, Radboud University, Nijmegen, Netherlands, 7Hematology, approximately 5 to 10% of newly diagnosed CLL cases. S.Orsola-Malpighi Hospital, Bologna, Italy, 8Hematology, Helsinki Patients with this abnormality have a poor prognosis after University Central Hospital, Helsinki, Finland, 9Hematology, VU chemo-immunotherapy. According to current guidelines, allo University Medical Center, Amsterdam, Netherlands, 10Hematology, HCT is recommended in 17p- CLL cases as part of the first- or University Hospital Leipzig, Leipzig, 11Hematology, Universita¨tsklini- second-line treatment. Oral drugs, which inhibit down-stream kum Wu¨rzburg, Wu¨rzburg, Germany, 12Hematology, Institut Paoli signalling of the B-cell receptor (Idelalisib & Ibrutinib) have Calmettes, Marseille, 13Hematology, Hoˆpital Haut-leveque, Pessac, recently been approved for this subset of patients and very 14Hematology, CHU Lapeyronie, Montpellier, France, 15Hematology, potent BCL2-Inhibitors are under clinical development. In University of Freiburg, Freiburg, 16Heatology, Universita¨tsklinikum 2010, the EBMT and the ERIC started a non-interventional Ulm, Ulm, Germany, 17Hematology, Erasmus MC-Daniel den Hoed study, to evaluate the outcome of alloHCT in 17p-CLL. Here we Cancer Centre, Rotterdam, Netherlands, 18Hematology, Karolinska report results on MRD clearance from this study. Institutet, Stockholm, Sweden, 19Hematology, Hospital Saint Antoine, Patients & Methods: Major eligibility criteria were 17p- CLL in Paris, France, 20Hematology, University Hospital Eppendorf, Ham- remission after first-line therapy or treatment of relapse, age below burg, Germany 70 years, availability of an HLA-compatible related or unrelated donor with up to one HLA-mismatch at HLA-A, -B, -C or DRB1. The Background: Autologous stem cell transplantation and the primary objective was to determine progression-free survival. development of new agents with potent anti-tumor activity

S108 have considerably improved the survival of multiple myeloma sub-optimal responses. After TKI therapy failure has been (MM) patients. However, there is still a high risk of relapse demonstrated, the decision to proceed with allogeneic HSCT mainly due to the inability of these agents to cure and should be based on the risk of the transplant (EBMT risk score) eliminate definitively the MM cells. Allogeneic hematopoietic and the likelihood of responding to a different TKI (and its long stem cell transplantation (allo-HSCT) is a potentially curative term side-effects). Clonal evolution, failure to achieve at least treatment particularly for patients with high risk factors but its mCyR to Imatinib, high Sokal score, loss of a previously achieved use is still controversial. CHR, mutations resistant to 2nd generation TKI and progression The objective of this study is to describe the context of use of to accelerated or blast phase are some of the factors to be allo-HSCT for MM in Europe within EBMT centers over more considered. The situation is slightly different when failure occurs than two decades with the evaluation of different outcomes. after an initial long period of good response (complete Material and methods: We included in this study a total of cytogenetic remission, molecular remission). The relapse of 7333 patients who received allo-HSCT between January 1990 CML while during on TKI therapy often involves one or more and December 2012, 4539 (62%) males and 2794 (38%) females mechanisms or resistance, including abl mutations. The like- with a median age at allo-HSCT of 51 years (range: 18-78), of lihood of responding to a second line TKI can be predicted which 4726 (64%) have been transplanted after year 2004. We based on parameters of the initial response. In any case, identified 6 groups in this population, patients who received assessment of the response to the second line TKI should be allo-HSCT upfront after induction therapy (Group 1, N ¼ 1924), done rapidly (within 6-12 months) and in case of absence of a patients who received allo-HSCT maximum 8 months after single second CCR or MMR, patients with an EBMT score of 0-2 should auto-HSCT (Group 2, N ¼ 2004), patients who received allo-HSCT proceed to allogeneic HSCT. For patients with higher EBMT later than 8 months after single auto-HSCT (Group 3, N ¼ 1589), score, the same factors should be taken into consideration. patients who received allo-HSCT maximum 8 months after Prior exposure to Imatinib does not seem to impact negatively double auto-HSCT (Group 4, N ¼ 589), patients who received on transplant related mortality, although information regard- allo-HSCT later than 8 months after double auto-HSCT (Group 5, ing the pre-SCT use of Dasatinib and Nilotinib is lacking. The N ¼ 931), and finally patients who received allo-HSCT after EBMT is conducting a prospective study analysing the impact having received at least 3 different HSCT (Group 6, N ¼ 296). of TKI therapy with one or more second generation TKI on all Results: The upfront use of allo-HSCT was seen to decrease transplant outcome. It has recruited over 450 patients and the after year 2000 to represent 12% of allo-HSCT performed in results are expected soon. 2012 while the peak of allo-HSCT use directly after 1 auto- Reduced intensity regimens have decreased the toxicity of HSCT (within 8 months) was around year 2004 to attend 19% allogeneic SCT and T cell depletion strategies have successfully of usage in 2012. Remarkably, allo-HSCT was moreover used at reduced the risk of GVHD, but there is still a high relapse rate the highest rate during the last years later than 8 months after in CML patients after T cell depletion. Imatinib and, to a lesser single auto-HSCT which could be translated in a context of extent, Dasatinib and Nilotinib have been used to successfully relapse post- first auto-HSCT to reach 33% of usage in 2012. postpone the need for DLI in this context and to treat relapse The usage according to groups 4, 5 and 6 was 14%, 17% and of CML at different stages after SCT. However, despite 5% in 2012 respectively. common clinical practice treating relapse with TKI, the infusion The median overall survival (OS) for groups 1, 2, 3, 4, 5 and 6 was of donor lymphocytes remains the standard of care and is 33, 69, 25, 25, 23 and 15 months respectively with a 5 years OS necessary to obtain long term molecular remissions. probability of 39%, 53%, 33%, 31%, 29% and 23% respectively; Progression to accelerated phase or blast crisis whilst on the median progression-free survival (PFS) was 45, 39, 21, 22, 21 Imatinib is indicative of a clinical situation that is incurable and 13 months respectively with a 5 years PFS probability of without allogeneic SCT. For those patients of a suitable age and 43%, 42%, 26%, 28%, 24%, and 15% respectively. The cumulative with a suitable donor every effort should be made to achieve a incidence of transplant-related mortality for the 6 groups at 3 second CP (either with conventional AML-like chemotherapy or years was 36%, 20%, 32%, 33%, 36% and 35% respectively. The with new TKI). Once obtained, an allogeneic SCT should be use of reduced intensity conditioning was associated with a performed as soon as possible, since responses are short-lived. significantly better OS only in group 2 compared to myeloa- Disclosure of Interest: None declared. blative conditioning with a median OS of 76 months versus 45 months (P ¼ 0.002) respectively. Year of transplantation before WP028 or after 2004 did not influence on outcomes. Role of allogeneic SCT in low risk MDS: A Retrospective Conclusion: This large retrospective study shows different ways Study on Behalf of the CMWP of the EBMT of using allo-HSCT for MM in Europe over a defined time period, 1,* 2 3 4 5 it describes the different expected outcomes in each case. Allo- M. Robin , R. Porcher , W. Zinke , A. Van Biezen , L. Volin , G. Mufti6, C. Craddock7, J. Finke8, C. Richard9, J. Passweg10, HSCT has not found it place yet in the treatment course of MM 11 12 13 14 15 patients and the debate should continue based on advantages A. Peniket , J. Martens , G. Sucak , T. Gedde-Dahl , A. Vitec , A. Nagler16, D. Blaise17, D. Beelen18, N. Maillard19, and disadvantages showed for each group of patients. 20 21 22 23 Disclosure of Interest: None declared. R. Schwerdtfeger , S. Iacobelli , T. De Witte , N. Kroger on behalf of CMWP 1Hoˆpital Saint-Louis, 2Hoˆpital Hotel Dieu, Paris, France, 3Medizi- WP027 nishe Universitat, Graz, Austria, 4EBMT data office, Leiden, Nether- The current role of allogeneic HSCT in the management of CML lands, 5University Central Hospital, Helsinki, Finland, 6King’s College E. Olavarria1,* Hospital, London, 7Queen Elizabeth Hospital, Birmingham, United 1Haematology, Hammersmith Hospital, London, United Kingdom Kingdom, 8Universitatis klinikum, Freiburg, Germany, 9Hospital de Valdecilla, Santander, Spain, 10University Hospital, Basel, Switzer- Hematopoietic stem cell transplantation (HSCT) was intro- land, 11Radcliffe Hospital, Oxford, France, 12Uz Gasthuisberg, duced as treatment for patients with CML in the late seventies Leuven, Belgium, 13Gazi University, Ankara, Turkey, 14RiksHospitalet, of the last century. HSCT gained rapid acceptance and by 1999 Oslo, Norway, 15institute of Hematology and Blood Transfusion, CML was the most frequent indication for an allogeneic HSCT Prague, Czech Republic, 16Tel-Aviv University, Tel-Aviv, Israel, 17IPC, worldwide. However, the introduction of TKI changed the Marseille, France, 18University Hospital, Essen, Germany, 19CHU, landscape completely. TKI are the standard therapy. Poitiers, France, 20Center of Bone Marrow Transplantation, Little information is available on how to proceed in patients who Wiesbaden, Germany, 21Universita tor Vergata, Roma, Italy, failed to respond to TKI and who have an available donor and 22University Medical Centre St Radboud, Nijmegen, Netherlands, are otherwise good candidates for transplantation. A new 23University Hospital, Hamburg, Germany concept is emerging: TKI therapy should be exploited and maximised for all patients from diagnosis (with a judicious use of Introduction: HSCT is the only curative treatment in patients all available TKI) in order to avoid and minimise failure and with MDS. Indeed, HSCT is mainly indicated and performed in

S109 the higher risk MDS. Actually, some lower risk patients have increased utilization of reduced-intensity conditioning regi- poor prognostic features leading to propose the transplanta- mens, which have extended the indication for HSCT to older tion before they evolve to a higher risk. In this registry study age groups. This is particularly relevant for patients with MDS from the CMWP, we analyzed outcome of patients who were as myeloablative HSCT has typically not been used in elderly diagnosed ‘‘low risk MDS’’ and who finally were transplanted patients, owing to advanced age, comorbidities and inade- without evolving to a higher risk. As more and more of these quate performance score. patients are proposed to the transplantation, their survey may Current recommendations on alloHSCT in patients with MDS give information about their prognostic risks. are usually based on data from nonrandomized studies, as well Materials (or patients) and methods: All adult patients as cohort studies. Disease risk scored according to the IPSS(-R), transplanted between 2000 and 2011 and registered in the age, and presence of comorbidity graded according to the EBMT registry could be included if they have a ‘‘low risk’’ MDS Hematopoietic Cell Transplantation Comorbidity Index were at time of diagnosis and at time of transplantation. Endpoints recognized as the most relevant clinical variables to be were estimated using usual method taken into account considered in order to judge a patient eligible for alloHSCT. Fit compating risk. Cox proportional hazard model were used to patients up to age 65 to 70 years and beyond with IPSS test the potential risk factors. Missing data were handled intermediate-2 or high risk and those with IPSS intermediate-1 through multiple imputations by chained equations methods. risk with excess blasts or poor-risk cytogenetics are candidates Results: 291 patients met the inclusion criteria: 126 women for alloHSCT. and 165 men. Median age at diagnosis was 53 years and inter- On the basis of the available evidence, intensive chemother- quartile range (IQR) from 44 to 59. The majority of patients apy should be administered to those patients with 10% or have refractory anemia or refractory cytopenia with multi- more bone marrow blasts who are candidates for allogeneic lineage dysplasia (66%), while one third of patients have SCT within a clinical trial or a prospective registry. Similarly, the refractory anemia with excess blasts. Most patients were evidence available so far does not allow recommendation on intermediate-1 (80%) and required transfusions before the the use of hypomethylating agents for this purpose outside transplantation (84%). Median age at time of transplantation clinical trials or prospective registries. was 55 years (IQR: 46-60). Median time from diagnosis to On the basis of the available evidence from prospective transplantation was 11 months (IQR: 7-22). Donor was an HLA randomized trials, peripheral blood stem cells are the matched sibling in 122 (42%) patients and an unrelated donor preferred source of stem cells for alloHSCT from an HLA- in the remaining patients. The preferred source of stem cells matched donor in patients with MDS. was peripheral blood stem cells (PB) (78%) followed by bone On the basis of evidence from prospective RCT, no specific marrow (19%) and cord blood (3%). Conditioning regimen recommendation can be given on the best myeloablative consisted in a reduced intensity conditioning regimen in the conditioning regimen. For MDS patients with a contraindica- majority of patients (59%) and 58% received an in vivo T tion to a standard myeloablative preparative regimen due to depletion.PFS and OS at 3 years were 52% (46-59) and 57% comorbidity, RIC alloHSCT should be considered, preferably (51-64). Cumulative incidence of grade II-IV acute GVHD and within a clinical trial. chronic GVHD were 29% (24-34) and 44% (38-50) while non- Based on the current guidelines the task force of 7 experts relapse mortality and relapse rates were 31% (25-37) and 17% developed 61 HSCT scenario’s for patients with MDS which (13-22). Multivariate analysis with original data set (excluding have been evaluated and discussed by all 22 experts during missing data) found the following factors as poor prognostic summer 2014. The main topics for these scenarios were: for PFS: ageo35 years (Hazard ratio (HR): 4.22, P ¼ 0.009) selection of MDS patients based on IPSS-R at diagnosis and at or445 years (Po0.05), blast count in bone marrow45% (HR: later time points (immediate versus delayed alloHSCT), 1.67, P ¼ 0.05), bone marrow (HR: 2.18, P ¼ 0.003) or cord blood intensity of conditioning regimen, pre-conditioning treatment, (HR: 5.28, P ¼ 0.014) as sources of stem cells rather than PB and type of donor (standard versus nonstandard|). CMV serostatus positive for the recipient and negative for the This resulted in a second round of 81 scenario’s both adapted donor (HR: 2.50, P ¼ 0.002) while transfusion before the and new scenario’s which are currently evaluated by the transplantation (HR): 0.51, P ¼ 0.013) and T-depletion (HR: expert panel members. These scenarios will be discussed in 0.60, P ¼ 0.43) were protective. The second multivariate February 2015 and the outcome, including persisting no analysis included all patients with imputed datasets showing conclusive scenarios will be presented at the annual meeting similar results. of the EBMT. Conclusion: To conclude, outcome after HSCT in patients with Disclosure of Interest: None declared. lower risk IPSS are better than those observed in higher risk. In favorable transplant condition, expected OS reaches 70% which could be a valid option in some lower risk patients presenting some ‘‘high risk factors’’ as poor molecular biology or resistance to agents stimulating erythropoiesis. Cellular Therapy & Immunobiology Disclosure of Interest: None declared.

WP029 WP030 Recommendations on the use of alloHSCT for patients with A Multi-Antigen Specific T Cell Product for the Prevention MDS and chronic myelomonocytic leukemia: prepared by of Viral Infections and Tumor Relapses Early after 22 members from an expert panel from EBMT Chronic allogeneic stem cell transplantation Malignancies Working Party, European LeukemiaNet and I. Jedema1,* MDS Foundation 1Department of Hematology, Leiden University Medical Center, T. De Witte1,*, G. Mufti2, D. Bowen3, L. Malcovati4, Leiden, Netherlands D. Niederwieser5, I. Yakoub-Agha6, M. Robin7, N. Kro¨ger8 1Radboud University Medical Center, Nijmegen, Netherlands, Allogeneic stem cell transplantation (alloSCT) is often applied 2King’s College, London, 3Leeds Teaching Hospitals NHS Trust, in the treatment of patients with hematological malignancies. Leeds, United Kingdom, 4Fondazione IRCCS Policlinico S. Matteo, Donor T cells directed against minor histocompatibility Pavia, Italy, 5University of Leipzig, Leipzig, Germany, 6CHRU, Lille, antigens (MiHA; foreign peptide recognized in self-HLA) and 7Hopital Saint-Louis, Paris, France, 8University of Hamburg, tumor associated antigens (TAA; self-peptide recognized in Hamburg, Germany self-HLA) can mediate the therapeutic graft versus leukemia (GVL) effect in the HLA-matched alloSCT setting. Early AlloHSCT is an, increasingly used, curative treatment option for application of donor T cells after alloSCT often results in graft patients with MDS. This increase can be attributed in part to versus host disease (GVHD). This can be prevented by T cell

S110 depletion of the graft. However, patients treated with a T cell extraordinaire efficacy of CAR-T cells in lymphoid tumors (CLL, depleted transplantation are prone to opportunistic viral ALL and NHL) and through strategic partnerships with big infections and disease relapses. In this study (T control, EU pharmas or the foundation of highly-innovative start-ups are FP7), we aim to treat patients early (6-8 weeks) after a T cell moving towards the consolidation of these results and their depleted alloSCT prophylactically with the infusion of a multi- exportation to other disease contexts (AML, MM, HL, solid and antigen specific T cell product to restore anti-viral immunity pediatric tumors). Several European centers are actively and support the GVL effect. This multi-antigen specific T cell involved in the design, development and validation of product consists of T cells directed against MHC class I innovative CARs. During the presentation, the major critical restricted peptides of CMV, EBV and adenovirus, HLA-A2 issues, including limited funding, regulatory hurdles, the role restricted TAA peptides (WT1, RHAMM, NY-eso, Proteinase 3) of patient and professional advocacy, that should be tackled and the MiHA HA-1 h. Previous research showed that high for the full exploitation of this technology in Europe will be avidity memory virus specific T cells can be easily enriched presented and discussed. from blood of seropositive healthy donors. However, the Disclosure of Interest: None declared. isolation of TAA and MiHA specific T cells is more complicated due to the extremely low precursor frequencies. Moreover, WP032 high avidity, self-HLA restricted TAA specific T cells may have Comparison of cord blood and non T depleted related been deleted during thymic selection. The reversible strepta- haplo transplant in adults with acute leukemia mer technology and magnetic bead isolation allows purifica- 1,2,* tion of minimally manipulated T cells from donor PBMC using A. Ruggeri 1He´matologie Clinique et The´rapie Cellulaire, Hoˆpital Saint- the CliniMACS under Good Manufacturing Practice (GMP) 2 conditions. Multiple specificities can be enriched in one Antoine, Eurocord Office, Hoˆpital Saint-Louis, Paris, France isolation procedure. To confirm the presence of TAA and MiHA specific T cell populations, additional streptamer Unrelated cord blood transplantation (UCBT) and unmanipu- enrichments were performed. The TAA and MiHA specific lated haploidentical stem cell transplantation (Haplo) are T cell populations were clonally isolated and expanded, alternative options to treat patients with high risk acute evaluated for CD8 and tetramer positivity and screened for leukaemia. Both strategies have shown encouraging outcomes antigen specific reactivity measured by cytokine release (IFN-g in more recent years. UCBT has been used for over twenty five and GM-CSF) after 24 hours of stimulation with TAP deficient years in both children and adult settings. Cord blood is safe for T2 cells loaded with the relevant peptide in a titration from the donor and allows proceeding to transplantation relatively 10^-11M to 10^-5M. In large scale validation runs (n ¼ 3) we quickly because donor selection is done based on the purified up to 12 viral, TAA and MiHA specificities out of inventory of units already available in the cord blood banks. Z500*10^6 donor PBMC in one procedure. As expected, the Moreover, there is the possibility of performing a successful main portion of this immediately clinical applicable multi- transplant with a higher degree of HLA incompatibility than antigen specific T cell product (purity of Z98%) comprised of allowed with other stem cell sources. Nonetheless, the use of different viral specificities. However, we were able to confirm UCBT in adult patients has been reported as limited due to the that the remaining part of the product contains T cells directed low stem cell content in a single cord blood unit. The use of against TAA and MiHA by performing subsequent individual double UCBT and reduced intensity conditioning regimen streptamer enrichments: when starting with 500*10^6 donor (RIC) in more recent years has helped overcome this limitation. PBMC, all TAA and MiHA specificities could be enriched to On the other hand, haploidentical donors are readily available detectable frequencies (1-78%) after 2 or 3 enrichments. for collection and also for subsequent transplants and/or DLI Among these TAA specific T cells were clones of intermediate donations when needed. Historically, haploidentical trans- avidity recognizing 10^-7M peptide despite the anticipated plants were performed using a ‘‘megadose of CD34 þ selected self-tolerance against these antigens. As expected, the graft’’ after ex-vivo depletion of T-cells to avoid severe GVHD, HA-1 h clones displayed high functional avidity reflected by however this approach was associated with high risk of graft recognition of peptide-loaded T2 cells in the pM range. failure, and high incidence of relapse. Other approaches, such This illustrates that intermediate avidity TAA-specific as additional post-transplant cell-therapies and optimization of and high avidity HA-1 h specific T cell clones can be conditioning regimens helped to partially overcome the enriched from healthy donors and that these cells may have pitfalls of the previous T-depletion procedures. Recently, the therapeutic potential. In conclusion, we are able to generate use of unmanipulated, non ex-vivo T cell depleted Haplo have from donor PBMC a highly purified multi-antigen specific T cell been used with different platforms for GvHD prophylaxis product for clinical application. Besides the main component giving encouraging results. Up to date, no studies are available of MHC class I restricted viral specific T cells, we have comparing the outcomes of UCBT and Haplo for adults with demonstrated that this product also contains proliferative high leukemia. With this background, we analyzed, retrospectively, avidity MiHA specific T cells and TAA specific T cells of patients with acute lymphoblastic leukemia (ALL) and de-novo intermediate avidity. acute myeloid leukemia (AML) receiving either UCBT (n ¼ 928) Disclosure of Interest: None declared. or unmanipulated Haplo (n ¼ 518) reported by EBMT centers from 2007-2012. Compared with UCBT recipients, Haplo patients were more likely to have AML (69% versus 40%, P ¼ WP031 Disclosure of Interest: None declared. A roadmap to the development of CAR-T cell immunotherapy in Europe A. B. 1,* WP033 1Innovative Immunotherapies Unit, Division of Immunology, Retrospective and non-interventional prospective studies Transplantation and Infectious Disease, Vita-Salute San Raffaele on the immunobiology of HSCT University, Milano, Italy A. Velardi1,* 1Bone Marrow Transplantation Unit, Division of Hematology, CAR-T cell immunotherapy has the potential to revolutionize Dept. of Medicine, University of Perugia, Perugia, Italy the way hematological, and possibly solid cancers, are treated. It is a one-time transformative therapy, by which autologous T The incredible advancements in the understanding of the cells are genetically targeted to the patient’s own tumor cells molecular and cellular mechanisms of HSCT in experimental thanks to the expression antibody-like chimeric antigen systems have not translated yet in significant changes in the receptors. Despite these promises, the implementation of overall practice of allogeneic HSCT. The former Immuno- CAR-T cell immunotherapy in Europe is yet to come. In the US biology, now Cell Therapy and Immunobiology, Working Party many academic centers have pivotally demonstrated the of the EBMT has launched different registry-based studies

S111 with the objective of exploring innovative biomarkers for due to a combination of the availability of safe and effective predicting, and potentially influencing through tailored biological therapies and less sustained responses to HSCT. immune intervention, the clinical outcome of HSCT. Two Activity has been country specific and the influencing factors combined retrospective studies aim at determining the need further analysis. The activity of allogeneic HSCT remains predictive value of NIMA/IPA mismatches (PI J. Van Rood) relatively low and largely restricted to paediatric practice. and of immune biomarkers (PI A. Bondanza), respectively, in Publication of ADWP guidelines and large clinical trials in the HLA-haploidentical transplantation in the period 2000-2012, last several years appears to be having an impact on activity. when procedures of ex vivo manipulation were predominant. References A non-interventional prospective study aims at investigating Snowden JA et al. Haematopoietic SCT in severe auto- the role of KIR alloreactivity (PI A. Velardi) in the same patient immune diseases: updated guidelines of the European population, but from 2013 on, when the use of an Group for Blood and Marrow Transplantation. BMT. unmanipulated graft is usually preferred. Another non-inter- 2012;47:770-90. ventional prospective study aims at studying the influence of Alexander T et al. HSCT for severe autoimmune diseases: thymic activity measured by TREC values pre-transplant (PI A. consensus guidelines of the European Society for Blood and Toubert) in different types of HSCT (sibling, MUD, haplo, cord) Marrow Transplantation for immune monitoring and biobank- from 2013 on. The design and, when available, the initial ing. BMT; 2014 Nov 10. doi: 10.1038/bmt.2014.251. results of these studies will be presented and discussed. Van Laar JL and Farge D et al. Autologous hematopoietic stem Disclosure of Interest: None declared. cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis. JAMA 2014; 311: 2490?98 Mancardi GL et al. Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a phase II trial-ASTIMS. Neurology 2015 in press. Autoimmune Diseases Disclosure of Interest: None declared.

WP035 WP034 From Autoimmunity to auto-inflammation EBMT Autoimmune Diseases Working Party (ADWP) M. F. McDermott1, D. McGonagle1,* Database: Activity 1994–2014 1Leeds Musculoskeletal Biomedical Research Unit, The Leeds J. Snowden1,*, M. Badoglio2, D. Farge3 Teaching Hospital NHS, Leeds, United Kingdom 1Department of Haematology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, 2EBMT Study Office, 3Unite´ de Abstract: Historically, the large spectrum of non-infectious Me´decine Interne et de Pathologie Vasculaire, UF04, Hoˆpital ‘‘inflammation against self’’ related disorders were viewed as St Louis, AP-HP, Paris, France autoimmune whereby B and conventional T cells of the adaptive immune lineages were the main cellular players in Originally supported by animal models and serendipitous case disease expression. Based on genetic insights from monogenic reports, haematopoietic stem cell transplantation (HSCT) has inflammatory diseases, we proposal that "inflammation against been evolving since 1994 as a specific treatment for patients self" be viewed along an immunologic disease continuum with autoimmune disease (ADs) refractory to conventional (IDC), with genetic disorders of adaptive and innate immunity treatments. Along with the establishment of the EBMT-ADWP at either end. Innate immune-mediated diseases may result in database, multidisciplinary guidelines were published from an tissue destruction without evident adaptive immune early stage to advise on selection and management of patients responses and the term ‘‘autoinflammation’’ was originally and these have recently been updated for both clinical and used to designate these non-autoimmune diseases. Within a laboratory practice (Snowden et al. 2012, Alexander et al. 2014). specific disease entity, disorders are situated along this IDC Randomised controlled trials (RCTs) have also been conducted and within a given disease diagnosis there is considerable under the EBMT ADWP (ASTIS, ASTIC and ASTIMS). Despite immunological heterogeneity with, for example, some types of international guidelines and RCTs, the uptake of this approach lupus being more autoimmune and others more innate has varied between countries and individual HSCT units, both immune driven. Innate immunity has been demonstrated in overall and specifically in respect to individual ADs. The aim of polygenic disorders, particularly Crohn’s disease (CD). this presentation is to summarise of the registrations of EBMT A genetic overlap exists between CD and some major database of HSCT for AD from the first patient treated in 1994 histocompatibility complex (MHC) class I-associated diseases, to the current status as of November 2014. including psoriasis; these MHC-1 associated diseases seem to Among 1793 HSCT procedures there were 1665 patients represent a true intermediate between autoinflammation and undergoing autologous HSCT, with median age 37 years (3-76) autoimmunity. Conversely, classical autoimmune diseases, and 126 pts undergoing first allogeneic HSCT, with median with autoantibody and MHC class II associations, including age 13 years (o1 to 57). Patients were registered from 240 celiac disease and rheumatoid arthritis (RA), have adaptive centres in 38 countries, 61% were female, 12% were o18 and immune genetic associations, including Cytotoxic T-Lympho- 46 patients had undergone 2nd or 3rd HSCT procedures. cyte Antigen-4 (CTLA4) and PTPN22 and these collectively are Indications included 645 patients with multiple sclerosis (MS), linked to autoantibody production that predates disease. This 544 pts with connective tissue disorders, 176 patients with proposed classification is clinically relevant, because innate inflammatory arthritis (IA), 48 patients with vasculitis, 168 immune-mediated disorders may respond to cytokine antag- patients with inflammatory bowel disease (IBD), 93 patients onism whereas autoimmune-mediated diseases respond with haematological immune cytopenias and 20 patients with better to anti-T and B cell therapies. Furthermore, the type 1 diabetes. The predominant countries of activity were etiopathogenesis of poorly defined "autoimmune" diseases, Italy, Germany, the Netherlands, UK, Sweden, Spain and such as juvenile idiopathic arthritis, may be inferred to have France, who made up the majority of the activity, although substantial innate immune involvement, based on response to other countries such as the Czech Republic, Greece, Belgium, IL-1 antagonism. With respect to cellular therapies for Switzerland and Australia have contributed significantly based inflammatory diseases, the best success of mesenchymal on per head of population. stem cells (MSCs) thus far has been in the graft-versus-host- Analysis of EBMT-ADWP database confirms that overall activity disease (GVHD) setting. Although an allogeneic mediated in HSCT for severe ADs is sustained despite the introduction of rather than an autoimmune disorder, GVHD shares features biological therapies. In some diseases, such as MS, SSc and IBD, with MHC-1 intermediate diseases in that CD8 T cells where long-term responses are confirmed, activity has been may prominently figure in disease expression. This presenta- increasing, whereas in others, particularly IA, activity has fallen tion will discuss the IDC concept with respect to

S112 cellular therapy development. Ref McGonagle D & disease frequency and outcomes are similar to those reported McDermott M. PLoS Medicine 2006. A proposed classification by other international centres. of the Immunological Diseases. http://journals.plos.org/ Disclosure of Interest: None declared. plosmedicine/article?id=10.1371/journal.pmed.0030297. Disclosure of Interest: None declared. WP036 Autologous stem cell transplantation for auto-immune WP035b diseases – The Australian experience from 1996-2014 Hematopoietic stem cell transplantation for autoimmune J. Moore1,* on behalf of on behalf of the Australian and New diseases in South America 1,* 1 1 Zealand Bone Marrow Transplant Society M. C. Oliveira Rodrigues , D. Moraes , J. Elias Dias , 1Haematology, St. Vincents Hospital, Sydney, Australia L. G. Darrigo-Jr2, C. E. Grecco3, A. Zombrilli1, A. B. Stracieri1, F. Pieroni4, N. Hamerschlak5, A. Ribeiro5, B. Simoes6 1 Abstract: Haemopoietic stem cell transplantation (HSCT) has Division of Cinical Immunology, UNIVERSITY OS SAO PAULO, been performed for severe resistant auto-immune diseases in 2Pediatrics Department, Ribeirao Preto Medical School— 3 4 Australia since 1996. Initial studies involved Rheumatoid University of Sao Paulo, Pediatrics Department, Department Arthritis prior to the availability of biologic therapies. Two of Internal Medicine, UNIVERSITY OS SAO PAULO, Ribeira˜o Preto, Phase II studies performed from 1996-2001 confirmed 5Hematology Department, Hospital Israelita Albert Einstein, Sao 6 profound but short-lived responses in Rheumatoid Arthritis Paulo, Hematology Department, UNIVERSITY OS SAO PAULO, sufferers. Since that time HSCT activity has predominantly Ribeira˜o Preto, Brazil been in patients with Systemic Sclerosis and Multiple Sclerosis. Overall there have been approximately 130 HSCTs performed Introduction: Activity on autologous hematopoietic stem cell for auto-immune diseases in Australia from 1996-2014. The transplantation (AHSCT) for autoimmune diseases has begun median age is 40 years (5-61), with 76% of recipients being in South America in 2001. The mainly involved centre at the females. Transplant related mortality is 1.5% (2/130 – both Ribeira˜o Preto Medical School, University of Sa˜o Paulo, Brazil, patients with scleroderma) and overall and disease free has been active on the field, especially concerning number of survival is currently being determined as part of a retro- transplanted patients, inovation (type 1 diabetes mellitus) and spective analysis. contributions to the scientific literature. Initially led by Dr. Ju´lio Disease indications for HSCT include: 44 Rheumatoid Arthritis Voltarelli, the Brazilian Autoimmune Disease Transplantation patients, 44 Multiple Sclerosis, 28 Scleroderma patients, 3 SLE Program includes five other transplant centres in the country, and 11 other indications. All but one patient received peripheral which also contribute providing patient data and discussing blood stem cells with the majority collected with cyclopho- joint protocols. sphamide and GCSF. Most patients have received cyclo/ATG or Materials (or patients) and methods: Transplant centres BEAM/ATG for MS whereas SSc patients received cyclo/ATG. known to be active on AHSCT for autoimmune diseases were Activity has increased significantly recently with a median of invited to update their reports on number and outcomes for 13 autografts performed per year from 2010-14 compared patients treated since 2001. Data were sent on completed with 2 per year from 2005-2009. Excel sheets and analyzed for descriptive statistics and survival Financing HSCT for these conditions remains a major concern curves. in the Australian hospital setting. Results: To date, 241 autoimmune disease patients have been Disclosure of Interest: None declared. included, 98% (n ¼ 238) of those effectively transplanted. Two of the Brazilian centres, the Ribeira˜o Preto Medical School (FMRP-USP, n ¼ 205) and the Hospital Israelita Albert Einstein WP037 (n ¼ 36) have the largest and longest experience on auto- Cellular therapy for autoimmune diseases in China logous transplantation in South America. Other four Brazilian L. Sun1,* centres have also included a total of 8 patients, out of which 6 1Department of Immunology & Rheumatology, The Affiliated proceeded to AHSCT. Similarly to the experience reported by Nanjing Drum Tower Hospital of Medical School of Nanjing international centres, the most frequently transplanted dis- University, Nanjing, China order was multiple sclerosis, corresponding to 50% (n ¼ 121) of the patients, followed by systemic sclerosis (26%, n ¼ 63), Autoimmune diseases (AD) are a group of heterogeneous type 1 diabetes mellitus (12%, n ¼ 29), and systemic lupus disorders including systemic lupus erythematosus (LED), erythematosus 3% (7). The remaining 22 patients comprise rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Takayasu’s arteritis (3), neuromyelitis optica (4), polymyositis scleroderma (SSc), multiple sclerosis (MS) and so on. The (1), Behc¸et’s (2), juvenile arthritis (1) and other neurological steroids and immunosuppressants have been mainly used to diseases (14). For multiple sclerosis, median follow-up after treat the AD. However, about 1/4 of patients were still resistant AHSCT was 6.6 (0.5-12) years, event-free survival at 5 years was to those conventional therapies even with biologic agents. Over 50% and transplant-related mortality (TRM) was 2.5%. When the past two decades, more than 2000 patients worldwide have patients were stratified by conditioning regimen, TRM was been treated by hematopoietic stem cell transplantation(HSCT) 14% (3/21) for the BEAM + anti-thymocyte globulin (ATG)- for the AD with good response. Recently, mesenchymal stem treated patients and zero (0/100) for the cyclophosphamide + cell transplantation(MSCT) has been explored in both AD ATG-treated patients. For systemic sclerosis patients, median models and humans with encouraging results and more safety. follow-up after AHSCT was 3.5 (0.5-10) years, event-free There are over 1000 patients with AD especially in lupus have survival at 4 years was 75% and transplant-related mortality been treated with allogeneic MSCT in China from 2007 to 2014 (TRM) was 5%. For type 1 diabetes patients, median follow-up though the majority of patients are from single-centre trials was of 5 (1.5–10) years, TRM was zero and five (17%) patients without randomised controlling. The efficacy rate of MSCT for remain completely insulin-free for mean of 4.9 years. lupus is about 60% including complete and partial remission Transplants for SLE have the highest TRM. Out of the 11 SLE with 20%-30% relapse in one year followup. Furthermore, the patients enrolled for AHSCT, 4 (36%) died due to complications transplantation related mortality of allogeneic MSCT is 0% due during the procedure. Median follow-up for this disease was 4 to without needed myeloablative cyclophosphamide(CTX) (1-11) years and disease activity-free survival was 40% in five precondition. A plethora of different mechanisms involved in years. therapeutic effect in a variety of autoimmune diseases Conclusion: In conclusion, South America is mostly repre- suggesting that mesenchymal stem cell play different immu- sented by the Brazilian activity on AHSCT for autoimmune noregulations and repaires when they arrived in different diseases and relevantly contributes to the field in number of inflammatory environment. transplanted patients. Except for type 1 diabetes mellitus, Disclosure of Interest: None declared.

S113 WP038 transplant (SCT), active and adoptive immunotherapy. The Updated recommandations for cardiopulmonary existence of a dose-response effect in epithelial tumors has evaluation, patient selection and treatment with been explored in a number of studies; however, the role autologous hematopoietic stem cell transplantation played by auto- and allo-SCT is still a matter of investigation. (AHSCT) in Systemic Sclerosis: The benefit of high-dose chemotherapy (HDCT) in selected D. Farge1,* on behalf of international collaborative working subgroups of patients has become clearer in germ cell tumor group (GCT), some subgroups of breast cancer, soft tissue sarcoma, 1Unite´ de Me´decine Interne et Pathologie Vasculaire, INSERM Ewing’s sarcoma, and medulloblastoma. UMRS 1160, Hopital St Louis, Paris, France The story of stem cell transplantation in ST demonstrates the importance of adopting an internationally co-ordinated Systemic sclerosis (SSc) is a rare disabling Autoimmune Disease approach to the investigation of this treatment modality. (AD) (prevalence 50-300 per million persons per year) due to There needs to be an increased emphasis on prospective trials excessive production and deposition of collagen in the skin, that are statistically robust and have well defined criteria for blood vessels and organs, which share some similarities with patient selection. Only these will be able to demonstrate GHVd. Severe SSc is associated with reduced life expectancy at 3 whether SCT, alone or incorporated into programs with novel to 5-years, which can be predicted according to the extent of therapeutic modalities, is worthwhile in patients for whom heart, lung and renal involvement (1). Two recent randomised conventional treatments have often limited impact on survival. controlled trials (RCTs) of autologous haematopoietic stem cell As far as the STWP activity is concerned, with a total number of transplantation (AHSCT) versus cyclophosphamide iv for SSc, 51.048 cases from 1990 to October 2014, the practice of auto- namely ASSIST (2) and ASTIS (3), have shown significant SCT in Europe is fixed in a steady-state of about 1.500 improvement in organ function, quality of life, disability scores procedures per year. Germany (8.042), France (7.605) and Italy and survivals and it is likely that the demand for AHSCT will (5.147) show the highest incidence of auto-SCT, with breast increase in the coming years. However, due to pre-existing vital cancer appearing to be the first solid tumor with a total of organ damage caused by SSc, the risks of transplant related 12.112 cases from 1990 to 2013, of which 9.271 for adult complications and treatment related mortality (TRM) are higher patients. However, the number of SCT in BC patients per year than in other autoimmune and malignant diseases. Early is being gradually decreasing since the boom in late-90 s, with selection of SSc patients for AHSCT with specific attention to a value of 55 cases for year 2013, although evidence of cardiac and pulmonary evaluation according to EBMT guidelines effectiveness has been documented especially for HER is important. In 2004, we had assessed existing data on negative disease. Germ-Cell Tumor (GCT) also exhibits a cardiotoxicity during AHSCT for autoimmune diseases, with remarkable total amount of SCT (8.650) with a higher special reference to systemic sclerosis, and proposed strategies incidence in adult patients (4.856); the number of transplants to reduce cardiac complications (4). Since then, larger use of MRI per year continues to be considerably elevated (532 cases for and right cardiac catheterization have enabled clinicians to year 2013). This said, some ongoing retrospective studies are improve cardiopulmonary function evaluation in SSc patients evaluating the long-term effects of HDCT followed by auto-SCT before HSCT and new algorythms have been developed. The in GCT patients. Moreover, a phase III perspective study has predictive value from heart and lung involvement on the the aim to compare the effects of HDC on GCT patients with outcome of HSCT for SSC (5) has been shown. These updated standard chemotherapy. For BC, ongoing prospective trials recommendations from the ADWP EBMT and members of the highlight the effects of neoadjuvant HDC and HSCT in triple- international working group will be presented. Thorough negative BC and in metastatic disease in comparison to evaluation of patients in centres with relevant specialist conventional chemotherapy. expertise, to exclude patients likely to have a high TRM, Disclosure of Interest: None declared. particularly patients with pulmonary hypertension and/or cardiac involvement, deliver transplantation and monitor outcomes. WP040 Such combined expertise can be provided in centres where Germ cell tumor: retrospective studies connective tissue disease specialists co-exist with preferably A. Necchi1,* JACIEorequivalentHSCTprogrammesandspecialistcardio- 1 pulmonary and pulmonary hypertension services. Patients Medical Oncology, Fondazione IRCCS Istituto Nazionale dei should be discussed by multi-professional teams and outcomes Tumori, Milano, Italy audited nationally and internationally by relevant disease groups. 1 Fransen J et al. Ann Rheum Dis 2011;70:1788–1792. Since the late Nineties the intensification of the dose of 2 Burt RK et al. (ASSIST). Lancet. 2011;378(9790):498-506. chemotherapy with bone marrow or hematopoietic stem cell 3 Van laar J and Farge D et al. JAMA. 2014;311(24):2490-2498. support held promise for patients with advanced and poor 4 Saccardi R et al. Bone Marrow Transplant. 2004;34(10): prognosis germ cell tumors (GCTs). High-dose chemotherapy 877-881. (HDCT) has nowadays a recognized indication in the salvage 5 Burt RK et al. Lancet. 2013;381(9872):1116-1124. setting of advanced GCTs and is steadily utilized worldwide. Disclosure of Interest: None declared. The picture is clear when considering the number of transplant per year as reported by the European Society for Blood and Marrow Transplantation (EBMT) network, where a steady increase since 2007 is obvious. An impressive proportion of relapsing or refractory patients exceeding 70% Solid Tumors in the second-line and 50% later were deemed to achieved a cure, although this apparent superiority over conventional- dose regimens is still hampered by the retrospective quality of available data and the lack of a randomized comparison with WP039 conventional-dose chemotherapy (CDCT). At present, the only Hematopoietic Stem Cell Transplantation in Solid Tumors randomized trial comparing CDCT with HDCT has been the F. Lanza1,*, P. Pedrazzoli2, A. Ravelli1, P. Brambilla1 on behalf of IT94 study in the pure second-line setting. It did not On behalf of EBMT Solid Tumor Working Party demonstrate an improvement for either disease-free survival 1Hematology, Istituti Ospitalieri di Cremona, Cremona, (DFS) and overall survival (OS) in the experimental arm, but 2Oncology, San Matteo Hospital, Pavia, Italy many still believe that this study did not definitely settle the HDCT role for GCT salvage. The Solid Tumor Working Party (STWP) is dedicated to pre- Furthermore, there are still pending issues, mainly concerning clinical, translational and clinical studies of cell therapy for ST, patient selection, mobilization strategy, and the inclusion of including autologous (auto) and allogeneic (allo) stem cell HDCT in the overall strategy of difficult-to-treat GCT.

S114 This is the reason why the EBMT-STWP is currently sponsoring regimens, and other improvements in supportive care have a retrospective study on the outcomes of HDCT administered reduced the transplant-related mortality rate to less than 1%. in the last 10 years in Europe. Also, in contrast to a generalized erroneous perception, The main objectives of the study are to enhance the morbidity and societal cost from ongoing non-transplant knowledge on the outcomes and prognostic factors in the therapy are not trivial. As a contribution to this field, the field, and to collect data on mobilization for GCT and the use GITMO STWP published the results of the HDC approach in a of plerixafor. large cohort of patients treated in Italy between 1990 and Since October 2013, data of 442 patients have been entered 2005 in both metastatic and HRBC setting (Martino et al BMT and results of the first analyses will be presented at the 2013, Pedrazzoli et al, BBMT 2014). Moreover, a retrospective meeting. EBMT STWP multicentre study of data available from the With respect to the first-salvage setting in particular multiple European registry on HRBC transplanted in Europe in the same uncertainties do actually persist, and an intercontinental period has been conducted; results will be presented at the phase 3 trial comparing four cycles of paclitaxel, ifosfamide, meeting. Taken together, the GITMO and the EBMT retro- and cisplatin (TIP) with the sequential TI-CE regimen spective studies suggest a role for HDC in the context of MBC (paclitaxel and ifosfamide for 1-2 cycles, followed by the triple and HRBC, especially in view of the fact that this procedure course of high-dose carboplatin and etoposide, TIGER trial) is can now be given safely and with the needed dose aimed to provide a landmark achievement. This trial, led in intensification, with both early and late minimal toxicity. In Europe by the European Organisation for the Research and particular, we believe that in the adjuvant setting of HRBC, Treatment of Cancer (EORTC) is expected to start in the first HDC may still represent a therapeutic option that can be quarter of 2015. proposed to patients harboring HER2-negative tumors and Finally, robust results of HDCT in special subset of patients like having gross involvement of axillary nodes those with a primary mediastinal nonseminoma (PMNSGCT) or Disclosure of Interest: None declared. female GCT are still pending. The EBMT is currently conducting a retrospective analysis on patients with female GCT who under- WP042 wentHDCTandwereregisteredintheEuropeandatabase,and A phase II randomized, open-label neo-adjuvant study of results are awaited. In the experience of EBMT, 59 patients with standard chemotherapy regimen compared to high dose extragonadal receiving HDCT have been reported. After a chemotherapy regimen with autologous stem cell median follow up of 58 months, 32% of them were alive and transplantation in patients with triple negative breast disease-free, including 14% of patients yielding a PMNSGCT. cancer Indeed some caveats in the available results should be D. Generali1,* on behalf of Working Party Solid Tumors recognized, mainly the very small number of patients. Also, 1 results with the use of the most effective high-dose salvage SS Terapia Molecolare e Farmacogenomica, AO Istituti regimens, namely double or triple course of high-dose Ospitalieri di Cremona, Cremona, Italy carboplatin an etoposide, are at a very preliminary stage. Disclosure of Interest: None declared. Abstract: Chemotherapy is known to reduce tumor burden, thus administering as high doses as possible would seem to be optimal. In a literature-based meta-analysis of WP041 13 randomized trials, it was found a statistically significant Breast cancer: retrospective studies benefit for event-free survival but not for OS. A recent review M. Martino1,*, P. Pedrazzoli2, F. Lanza3 on solid tumor trials concluded that there was no overall 1Azienda Ospedaliera BMM, Reggio Calabria, Hematology and benefit for the use of HDC. However, it was suggested that Stem Cell Transplant Unit, Reggio Calabria, 2Dept Onco- additional trials could consider HDC in patients with triple- Hematology, Fondazione IRCCS Policlinico S. Matteo—Pavia, negative primary breast tumors, because there were no Pavia, 3Hematology Institute, Hospital of Cremona, Cremona, targeted therapies for these patients. A review enclosing 14 Italy randomized trials in solid tumors and supported the evalua- tion of regimens of HDC with low mortality rates in future The clinical correlation between chemotherapy (CT) dose breast cancer trials for subgroups most likely to benefit. Our intensity, achieved either by increasing the single dose per study is multicentric, two arms, randomised, open-label study. cycle (ie, higher dose) or by reducing the intervals between Patients with primary triple-negative breast tumors will be cycles (ie, dose density), and outcome in breast cancer (BC) has evaluated for the enrolment and they will be randomised been described since the 1980 s. This led, along with phase II according to the following scheme: ARM A: EC for 4 Cycles studies apparently demonstrating significant favorable out- followed by docetaxel for 4 cycles; ARM B: ET for 4 Cycle comes compared with historical data, to the premature followed by HDC and AHST for 2 cycles. The aim is to compare acceptance of high-dose chemotherapy (HDC) with autolo- percentage of pathologic complete response (pCR) of the two gous hematopoietic progenitor cell transplantation (AHPCT) as regimens of treatment to evaluate which will induce the a treatment option both in the adjuvant and metastatic highest pCR among the two regimens. settings, with up to nearly 2000 patients per year undergoing Disclosure of Interest: None declared. this procedure in the mid-1990 s in Europe. Unfortunately, the vast majority of patients were treated outside of prospective randomized studies. At the turn of the century, in view of early WP043 reports of randomized trials not showing a significant overall Circulating tumor cells (CTCs) and Autologous survival (OS) benefit of HDC, the vast majority of medical hematopoietic stem cell transplantation in triple negative oncologists no longer considered this procedure an option. In metastatic breast cancer the era of great expectations for targeted drugs, data from J. M. Reuben1,*, M. Mego2, H. Gao1, N. T. Ueno3 randomized studies demonstrating an OS benefit of HDC for 1Hematopathology-Res, MD Anderson Cancer Center, Houston, high-risk breast cancer (HRBC), along with additional evidence United States, 2National Cancer Institute, Bratislava, Slovakia, of the benefit of intensified CT, did not change this attitude. 3Breast Medical Oncology, MD Anderson Cancer Center, Houston, Moreover, the two EBMT/MDACC meta-analyzes along with United States ‘‘modern’’ phase III studies suggest that HDC may still have a role in selected patients (Berry et al JCO 2011). HDC has Epithelial tumor cells in the peripheral blood, known as become less toxic over time and it should be considered a safe circulating tumor cells (CTCs), are an independent prognostic procedure. The introduction of myeloid growth factors after factor in metastatic breast cancer (MBC) patients treated by transplantation, the use of peripheral blood stem cells in place conventional dose chemotherapy. CTCs can migrate to the of bone marrow, modern, better-tolerated conditioning bone marrow microenvironment, where they are known as

S115 disseminated tumor cells (DTCs) and constitute a reservoir of To fulfill this aim, we have assessed the feasibility of obtaining, occult breast cancer. In patients for whom high dose selecting, characterizing and amplifying autologous tumor- chemotherapy (HDCT) without or with autologous hemato- specific cytotoxic T lymphocytes (CTL), generated by stimula- poietic stem cell transplantation (AHSCT) is planned, the tion of patients’ PBMCs with dendritic cells (DC) pulsed with cytokine granulocyte colony-stimulating factor (G-CSF) is apoptotic tumor cells. The preliminary results show that the routinely administered to mobilize hematopoietic progenitor generation of tumor-specific CTL suitable for ACT immuno- cells (HPC) from the bone marrow into the peripheral therapy is feasible from peripheral blood of patients with circulation, where they can be harvested for AHSCT. Both colorectal cancer. If successful, this strategy may prove useful HPC and CTCs express the chemokine receptor, CXCR4. Thus, for ACT in mCRC and other solid tumors. the mobilization of HPC, facilitated through interaction of its Disclosure of Interest: None declared. surface receptor CXCR4 and G-CSF, will also recruit DTCs from the bone marrow to the peripheral blood. Recently, CTC and CTCs undergoing epithelial mesenchymal WP045 transition (EMT-CTC) were found to be prognostic in MBC Perspectives of Immunothreapy in Solid Tumors patients receiving HDCT and undergoing AHSCT. In the P. Comoli1,*, S. Basso1, S. Secondino2, A. Gurrado1, P. Morbini 3, proposed study, we will assess the roles of CTCs and EMT- M. Benazzo4, F. Baldanti5, M. Zecca1, P. Pedrazzoli2 on behalf of CTCs on progression-free survival (PFS) and overall survival On behalf of The ‘‘San Matteo’’ Head and Neck Tumor (OS) in triple negative metastatic breast cancer patients. We Multidisciplinary Group will assess peripheral blood and apheresis samples for CTCs 1Pediatric Hematology/Oncology, 2Oncology, Fondazione IRCCS and EMT-CTCs using the AdnaTest Stem Cell/EMT2 kit from Policlinico San Matteo, 3Pathology, 4Otolaryngology, Fondazione AdnaGen that uses magnetic beads coated with antibodies to IRCCS Policlinico San Matteo, University of Pavia, 5Molecular EpCAM, EGFR and HER2 to capture the CTCs that will Virology Units, Fondazione IRCCS Policlinico San Matteo, Pavia, subsequently be subjected to qRT-PCR for the detection of Italy CTC- and EMT-CTC-related gene transcripts. The clinical relevance of these biomarkers in triple negative breast cancer Among the novel biologic therapeutics that will increase our patients receiving HDCT and AHSCT will be discussed. ability to cure human cancer and the complications associated Disclosure of Interest: None declared. with its cure in years to come, adoptive T cell therapy (ATCT) is one of the most promising approaches. Although this is a complex and challenging field, there have been major WP044 advances in basic and translational research resulting in Adoptive immunotherapy for metastatic solid tumors clinical trial activity that now affirm this promise. M. Bregni1,* Early trials have focused on the treatment of viral infections 1Department of Oncology, Ospedale di Circolo, Busto Arsizio, Italy and virus-related tumors developing in the immunocompro- mised host. Epstein-Barr virus (EBV)-associated malignancies The adoptive T-cell transfer (ACT) of a large number of ex-vivo offer a unique model to develop T cell-based immune expanded tumor-infiltrating lymphocytes (TILs) can signifi- therapies, targeting viral antigens expressed on tumor cells. cantly mediate tumor regression in patients with refractory In the last two decades, EBV-specific cytotoxic T-lymphocytes metastatic melanoma (Dudley ME et al, J Clin Oncol (CTL) have been successfully employed for the prophylaxis and 2005;23:2346-2357) and other solid tumors, most notably treatment of EBV-related posttransplant lymphoproliferative nasopharyngeal carcinoma and soft-tissue sarcoma. However, disorders. More recently, this therapeutic approach has been the extension of this strategy to other solid tumors is in most applied to other hematologic and solid tumors. The feasibility cases hampered by the difficulty of isolating TILs from tumors and efficacy of standard EBV-targeted CTL and EBV subdomi- other than melanoma, and of amplifying a sufficient quantity nant antigen-specific CTL treatment in phase I/II clinical trials of autologous tumor-reactive T cells, capable of preserving conducted in patients with advanced refractory NPC have been their cytotoxic capacity after expansion for therapeutic use. demonstrated by different groups. With the possible exception Moreover, the need to adopt good manufacturing practice of EBV-specific CTL for EBV-positive tumors, and tumor- (GMP) procedures for clinical use increases costs and limits infiltrating lymphocyte therapy for melanoma, clinical trials of applicability of this strategy in the clinic.Colorectal cancer is ATCT have so far only provided clear proof-of-principle that the third most common cancer worldwide (9% of all cancer objective clinical responses may be attainable. The results are incidence), and the fourth most common cause of death in the encouraging, although further improvements to the clinical developed Western countries. New drugs (irinotecan, oxalipla- protocols are clearly necessary to increase anti-cancer activity. tin) and new biologic agents have recently increased survival Recent studies demonstrating that normal human lympho- of metastatic disease: in detail, a humanized monoclonal cytes can be genetically engineered to recognize cancer antibody (bevacizumab) that targets vascular endothelial antigens and mediate cancer regression in vivo has growth factor, and monoclonal antibodies that inhibit the opened opportunities for enhancing and extending the ATCT epidermal growth factor receptor (cetuximab and panitumu- approach to patients with a wide variety of cancer types. mab). Although a clear association between tumor-infiltrating However, the high affinity for target antigens shown by some T cells and clinical outcome have been documented in of these cell products, that is responsible for some dramatic, colorectal carcinoma, active and adoptive immunotherapy durable clinical responses recently reported in hematologic do not play an important role in the treatment of mCRC. A cancer, is yet to be confirmed in the solid tumor setting. number of autologous and allogeneic tumor vaccines, ATCT offers a unique opportunity to restore antitumor and specifically against CEA and 5T4 antigen, have improved anti-pathogen immune surveillance, and it is therefore immune response in a large percentage of colorectal cancer conceivable that application of this strategy will increase in patients, but this has not translated into improved outcome. In the next few years. Despite the great potential, immunother- addition, in vitro studies performed on bulk TIL cultures apy still has a marginal role in the management of patients purified from mCRC patients did not demonstrate uniform lytic with cancer. This is due to limitations inherent to the activity against autologous cancer cells.It has recently reported technologies and products employed, and to the financial the feasibility of retrieving effector T cells from the peripheral and structural burden that are associated with cell therapy. blood of acute leukemia patients, and their utilization as Indeed, the extensive infrastructure needed for exploiting such effectors in ACT programs (Montagna et al., Int J Cancer approaches still restricts their use to academic centers with 2004;110:76-86). We have focused on the extension of this specific programs in the field. For progression to a widely adoptive cell transfer immunotherapy approach to colorectal used, effective and safe ATCT, cooperation in ATCT networks is cancer, by retrieving the tumor-reactive T cells from the crucial. Peripheral Blood Mononuclear Cells (PBMCs) of the patients. Disclosure of Interest: None declared.

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