European Blood And Marrow Transplantation Research Articles

Survey of European Blood and Marrow Transplant (EBMT) nurses to explore the current topical skin management of chronic cutaneous graft versus host disease in the real-world clinical environment.

To understand the current practice in relation to the management of topical therapy for cutaneouschronic Graft versus Host Disease (ccGvHD) and access to extracorporeal photopheresis (ECP) within European allogeneic haematopoietic cell transplantation centres by a survey of nurses. This was a multicentre cross-national study at eligible European Blood and Marrow Transplant centres. Eligibility required more than 30% of treated patients having allogeneic haematopoietic cell transplant. Centres performing only autologous stem cell transplants were excluded from the study. 12% of respondents were unaware of whether their centre had a policy or not for monitoring chronic cutaneous graft versus host disease. Over half had the affiliation of a dermatologist for referral, but only 19% had access to a specialist nurse. Patient education was routinely provided in most of the centres (86%). Results suggested as the severity of a patient's chronic cutaneous graft versus host disease increased, there was a reduction in the amount of topical emollients and steroids employed. Following topical therapies, systemic treatments, and other modalities such as ECP were employed with less focus directed towards topical care. Topical treatment is the backbone of any treatment paradigm for chronic cutaneous graft versus host disease, however, there is no universally agreed algorithm. Improved skin care may lead to a reduction in the amount of systemic therapy required, thus increasing patients' quality of life. There is little standardisation in the topical management of chronic cutaneous graft versus host disease, despite skin being the most cited organ affected by chronic graft versus host disease, this should be addressed.

Long-Term Outcome of Multiple Myeloma Patients Receiving Autologous Stem Cell Transplantation (ASCT) - Impact of Therapeutic Strategy Following ASCT

Introduction Despite all the therapeutic progress made in multiple myeloma (MM), the standard of care for eligible patients remains an intensive induction therapy followed by high dose melphalan and autologous stem cell transplantation (ASCT). Material and methods This present retrospective study included MM patients treated in Lyon between 1997 and 2020. All patients received induction chemotherapy followed by intensive chemotherapy and ASCT, with or without consolidation and maintenance therapy. Number and type of therapeutic lines administered for relapse after ASCT were analyzed. All data were reported in the European blood and marrow transplantation (EBMT) PROMISE registry. Statistical analysis Descriptive analyses were used for demographic variables, biological parameters, and treatment characteristics. Overall survival (OS) and progression-free survival (PFS) were presented using the Kaplan-Meier method and log-rank tests were performed to compare survival curves. Univariate and multivariate analyses were computed using Cox regressions and the multivariate analyses considered the variables for which the univariate ANOVA p-value was≤ 10%. Statistical analyses and graphics were computed with R v4.1.2, with the help of ‘survival’ and ‘ggplot2‘ packages. Results Before ASCT A total of 342 patients were included in the study (median 60 years (range: 28-73), 58% were male, 89.4% were diagnosed with a type III myeloma according to the Salmon and Durie classification. No genetic analysis was performed at that time. Most patients (92.5%) had a performance status (PS) of 0 or 1. The type of myeloma was heavy chain and light chain myeloma for 75.7% patients (68.9% of IgG kappa) and light chain myeloma in 23.1%. The median delay between diagnosis and ASCT was 4.8 months. Before ASCT, patients received an induction therapy with VTD in 54.1% of cases, VD in 30.1%, and more recently VRD in 16.1%. Disease status before ASCT was complete remission (CR) for 17.5% of the patients, partial remission (PR) and very good partial remission (VGPR) for 79.2% of patients and progressive disease or relapse for 3.0% of them. After ASCT The median duration of aplasia was 11 days. At day 100, the response was CR in 166 patients (50.5%), 182 patients (54.7%) received a consolidation treatment and 71 patients (20.8%) a maintenance therapy (Revlimid® for 90% of them). Overall, 227 (66.4%) patients relapsed. The median delay between ASCT and relapse was 22.5 months (0.89-229.13) and the median follow-up duration was 46.7 months (0.33-287.97). Among the 227 patients who relapsed, 6 patients were not treated, 79 patients (23.1%) received one chemotherapy line, 32 patients (9.4%) received two lines, 38 (11.1%) received 3 and 72 (21.1%) received at least 4 lines and up to 8. Overall survival and progression free survival The median OS was 132 [95% CI 110.6; NR] months from diagnosis and 122.8 [100.9; NR] months from ASCT. The median PFS was 39.35 [36.25; 43.37] months from diagnosis and 31.07 [28.42; 35.91] months from ASCT (Figure 1 A, B). In multivariate analysis on OS, the shorter aplasia duration (p<0.001) and consolidation and maintenance (p<0.001) were significantly associated with a significant better OS. The median OS was not reached from ASCT for patients who have received both consolidation and maintenance treatments and no death was reported. (Figure 1 C). For patients receiving chemotherapy lines for relapses after ASCT (Figure 1D) regardless of the number of lines the median OS was102.4 months and the 10-year OS probability was 45.6%. The OS of patients who received 3 lines of treatment was identical to that of patients who received one or 2 lines after ASCT. The median OS after 1 to 2 lines of chemotherapy after ASCT was not reached and was 127.15 months [70.6-NR] for those receiving 3 lines (Figure 4B). The OS of patients who received more than 4 chemotherapy lines after ASCT was significantly lower compared to the OS (p=0.0096) with a median [95%CI] OS of 85.5 months [65.61-106.15]. In conclusion this study showed the significant positive impact on OS of the association consolidation and maintenance. We have also studied the impact of number of chemotherapy lines and the impact on OS and PFS of kind of treatment will be discussed.

Low Toxicity and Disease Responses in Systemic AL-Amyloidosis Using an Yttrium-90 Labelled Anti-CD66 Monoclonal Antibody TLX66 As the Only Conditioning Prior to Autologous Stem Cell Transplantation

Despite the introduction of new therapies Systemic AL-amyloidosis (AL) remains incurable and the majority of patients will relapse. Autologous stem cell transplantation (ASCT) remains an important treatment option with improvement of organ function and survival in responding patients, however the toxicity of ASCT using conventional chemotherapy results in high morbidity and mortality limiting the application in this vulnerable patient group. We tested the use of a monoclonal anti-CD66 radiolabelled with yttrium-90, TLX66 (90Y-besilesomab) as the sole conditioning agent prior to ASCT in a phase I study in patients with AL. The study had full ethical and regulatory approvals (EudraCT 2015-002231-18; ISRCTN 13400668). The study consisted of three radiation activity levels, 30, 40 and 45 Mega Becquerels (MBq) per kg body weight with 3 patients treated at each activity level. Patients entered the study after fulfilling entry requirements and with informed consent. Prior to receiving the 90Y-besilesomab organ dosimetry and biodistribution were determined using the same anti-CD66 radiolabelled with indium-111 (111In-anti-CD66) with sequential gamma camera imaging. Estimated absorbed radiation to critical organs was determined from an established dosimetry model, organ radiation dose expressed in Gray (Gy). Radiation dose limits of 45Gy for the bone marrow and 15Gy for the liver were used as safety measures. Table 1 summarises patient details. The median previous lines of treatment were 2 (range 1-5) including three who had previous ASCT using high dose melphalan. The primary end-point was treatment related toxicity as determined using CTCAE v4.0. Haematological toxicities (cytopenia) were excluded as adverse events (AEs) unless considered life-threatening. Secondary end-points: Disease response determined by changes in clonal free light chain assay (FLCa), malignant plasma cell percentage in BM as determined by multi-colour flow cytometry; cardiac toxicity from NT-proBNP assay; overall survival and time to disease progression; biodistribution and dosimetry SPECT-CT imaging; engraftment using the European Blood and Marrow Transplant (EBMT) criteria for neutrophil and platelet engraftment. Results: Ten patients underwent dosimetry with 111In-anti-CD66, 9 received the 90Y-besilesomabwith infused activity determined by study cohort and patient body weight; one patient failed dosimetry with excessive hepatic uptake, two received reduced activity to keep the marrow dose within the 45Gy limit. There were no serious adverse events (SAE's) in the trial. There were 3 grade 4 AE's (mainly cytopenias during transplantation) and no SUSAR's were reported. A total of 41 grade 1-4 AE's were recorded. There were no transplant related deaths. All patients became profoundly cytopenic consistent with bone marrow suppression due to the targeted radiation. All patients engrafted with median neutrophils recovery by D+13 and platelets by D+11. Importantly, no patients experienced any mucositis or therapy related diarrhoea. All maintained oral nutrition. Only two patients experienced a fever post-transplant, neither were life-threatening. Table 2 summarises the estimated absorbed radiation dose to critical organs and disease responses. Of the 9 patients treated with 90Y-besilesomaband ASCT 7 had haematologic responses with 2 complete responses (CR), 5 partial responses (PR), 1 stable disease (SD) and 1 progressive disease (PD) as determined. Six of 8 evaluable patients showed a reduction in percentage of malignant plasma cells in the BM. The study collected data up to D+100 post-transplant but 2 patients showed continuing slow reduction in clonal FLCa beyond D+100 with 1 achieving a CR 5 months post-transplant. No radiation dose limiting toxicity was seen. No consistent changes were seen in NT-proBNP. Importantly no cardiac AEs were recorded. All patients are alive. The long term follow up data will be presented. Acknowledgement: The native anti CD66 MAb (Besilesomab) was provided by Telix Pharmaceuticals. TLX66 (90Y-besilesomab) was acquired by Telix Pharmaceuticals in 2021. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Primary vaccination in adult patients after allogeneic hematopoietic stem cell transplantation – A single center retrospective efficacy analysis

Allogeneic hematopoietic stem cell transplantation (alloHSCT) results in a loss of humoral immunity and subsequent risk for severe infections. Thus, re-vaccination is required but may fail due to incomplete immune reconstitution. We retrospectively analyzed predictors of immune response to primary vaccination applied according to the EBMT (European Blood and Marrow Transplantation Group) recommendations. Serologic response to vaccination against diphtheria (D), tetanus (T), Bordetella pertussis (aP) and Haemophilus influenzae (Hib) (administrated as combined DTaP-Hib-IPV vaccination) was studied in 84 alloHSCT patients transplanted between 2008 and 2015 (age at alloHSCT: 18.6–70.6 years). All patients with a relapse-free survival of ≥9 months, at least 3 consecutive vaccinations and absence of intravenous immunoglobulin administration within 3 months before and after vaccination met the primary inclusion criteria. Additionally, immunological response to a pneumococcal conjugate vaccine was analyzed in a subgroup of 67 patients. Patients’ characteristics at the time of first vaccination were recorded. Responses were measured as vaccine-specific antibody titers. Regarding DTaP-Hib-IPV vaccination, 89.3% (n = 75) of all patients achieved protective titers to at least 3 of the 4 vaccine components and were thus considered responders. 10.7% (n = 9) of the patients were classified as non-responders with positive immune response to less than 3 components. Highest response was observed for Hib (97.4%), tetanus (95.2%) and pneumococcal vaccination (83.6%) while only 68.3% responded to vaccination against Bordetella pertussis. Significant risk factors for failure of vaccination response included low B cell counts (p < 0.001; cut-off: 0.05 B cells/nl) and low IgG levels (p = 0.026; mean IgG of responders 816 mg/dl vs. 475 mg/dl of non-responders). Further, a trend was observed that prior cGvHD impairs vaccination response as 88.9% of the non-responders but only 54.7% of the responders had prior cGvHD (p = 0.073). The results demonstrate, that the currently proposed vaccination strategy leads to seroprotection in the majority of alloHSCT patients.

Global collaboration led by the EBMT Nurses Group

The success of a haematopoietic stem-cell transplantation (HSCT) programme relies heavily on appropriately trained and experienced nursing staff. The European Blood and Marrow Transplantation (EBMT) Nurses Group's mission is to enhance and value the nurse's role globally—supporting and sharing knowledge through communication, advocacy, research, training, and education. The group is dedicated to improving the care of patients receiving HSCT and works towards promoting excellence in care, through recognising, building upon, and providing evidence-based practice.

Upfront Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Idiopathic Aplastic Anemia: A Study on Behalf of the Saawp of EBMT

Upfront Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Idiopathic Aplastic Anemia: A Study on Behalf of the Saawp of EBMT

Outcome of Children Developing Grade III-IV Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

Acute graft versus host disease (aGvHD) remains one of the major causes of procedure-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Information on the outcome of pediatric patients experiencing this complication is limited. We conducted a retrospective registry-based analysis on children who developed grade III-IV acute GVHD and were reported to the European Blood and Marrow Transplantation (EBMT) registry. Included in the study were children below age of 18 years who were transplanted between 2004 and 2016 (n=28109). Of these children, 1968 experienced grade III-IV acute GvHD: 1370 were had malignancies, while 598 were affected by a non-malignant disorder (NMD). Median year at HSCT was 2009 for patients with malignancies and 2010 for patients with NMD. In this latter group, as expected, the median age at HSCT was lower (5.8 years), in comparison with those affected by malignancies (9 years). The donor was an HLA-identical sibling in 576 cases and an unrelated donor in 895 cases. Umbilical cord blood (UCB) was employed in 282 cases, while a relative other than a compatible sibling in 215 cases. Overall, 1075 patients were given bone marrow (BM), while 598 received peripheral blood stem cells (PBSC). A fully myeloablative conditioning regimen has been employed in 94% of patients with malignancies in comparison with 75% of children with NMD. As a post-transplant pharmacological GvHD prophylaxis, a different strategy of immune suppressive treatment have been used: it consisted in the association of Cyclosporine-A (CSA) and Methotrexate in 40%, CSA alone in 30% and CSA plus Mycophenolate mofetil in 10% of patients. Grade III aGvHD occurred in 1383 patients (70%), while grade IV aGvHD was diagnosed in 585 (30%). Chronic GvHD occurred in 48.2% and 49.3% of patients with malignant and NMD, respectively. It was extensive in 262 (26.8%) patients with malignancies and in 111 (28%) children affected by NMD. Within patients with malignancies, the 2-year Kaplan-Meyer probability of overall survival (OS) was 65.7% (confidence interval 95, 63 - 68.4). In this group, the cumulative incidence of non-relapse mortality (NRM) was 23.1%. Notably, the occurrence of GvHD was responsible of death in 228 patients (CI 14.5%). In the NMD cohort, the 2-year Kaplan-Meyer probability of overall survival (OS) was 67.8% (confidence interval 95, 63.8 - 71.9). Sixty-one patients died to GvHD, being the 2-year cumulative incidence of GvHD-related mortality 19%. These data indicate that the occurrence of grade III-IV aGVHD is associated with a dismal outcome also in pediatric patients. The main cause of fatality is represented by NRM, while leukemia recurrence affected outcome of a lower number of children. Thus, strategies aimed at preventing this immune-mediated complication and at optimizing its treatment are desirable.

Outcome of Children Developing Grade III-IV Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation: A Report on Behalf of the EBMT Paediatric Diseases Working Party

IntroductionAcute graft versus host disease (aGvHD) still remains one of the major causes of procedure-related morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Information on the outcome of paediatric patients experiencing this complication is limited. For this reason, we conducted a retrospective registry-based analysis on 2519 children who developed grade III-IV acute GVHD and were reported to the European Blood and Marrow Transplantation (EBMT) registry.Patients and methodsIncluded in the study were children below age of 18 years who were transplanted between 2004 and 2014. Median year at transplantation was 2009. Of these children, 826 children had a non-malignant disorder, while 1689 were affected by malignancies. The donor was an HLA-identical sibling in 707 cases and an unrelated donor in 1081 cases. Umbilical cord blood (UCBT) was employed as stem cell source in 396 cases, while a relative other than a compatible sibling was utilized in 202 cases. Overall, 1281 patients were given bone marrow (BM), while 800 received peripheral blood stem cells (PBSC).ResultsGrade III acute GvHD occurred in 1607 patients (64% of the overall population), while grade IV acute GvHD was diagnosed in 908 (36%). Chronic GvHD occurred in 649 patients (26 % of the overall number of children who developed grade III-IV aGVHD). It was extensive in 333 (13%) and of limited severity in 269 (11%). At time of last follow-up, 1341 patients were alive (53%), while 1178 were dead (47 %). Fifty-seven patients were lost to the follow-up. Relapse of the original disorder occurred in 219 children (19.7% of patients experiencing grade III-IV aGvHD). Transplant-related causes were responsible for the death of 902 patients (76.5%), while 6 (0.5%) patients developed a secondary malignancy. The 3-year Kaplan-Meyer probability of overall survival (OS) was 46.7% (confidence interval 95, 44.1-49.5) and 50.9% (confidence interval 95, 47.1-54.9) in patients affected by malignant and non-malignant disorders, respectively. Patients who received as stem cell source BM had a better outcome in comparison to those who received PBSC (3-year OS, 53.2 vs 40.4%, P<0.0001). In the overall cohort, in comparison to patients who developed limited cGvHD, the extensive form of the disease had a detrimental effect on the outcome, being the 3-year OS 74.2% and 41.6%, respectively (P<0.0001). In multivariate analysis, the only variables affecting overall survival were the age at transplant (P<0.0001) and the type of donor (sibling vs UD, CB, MMFD, P<0.0001). The 3-year Kaplan-Meyer probability of non-relapse mortality (NRM) was 37.4% (confidence interval 95, 34.9-39.9) and 45.9% (confidence interval 95, 42-49.7) in malignant and non-malignant disorders, respectively. Also in this case, use BM instead of PBSC seems to be an advantage, being the 3-year NRM 35.1% and 47.8%, respectively. In multivariate analysis, besides the age at transplant (P<0.0001) and the type of donor (sibling vs UD, CB, MMFD, P<0.0001), the use of a myeloablative conditioning regimen (MAC) chemo-based (P<0.0001) and the development of extensive chronic GvHD (P<0.0001), had a detrimental effect on NRM.ConclusionThese data indicate that the occurrence of grade III-IV aGVHD is associated with a dismal outcome also in paediatric patients. The main cause of fatality is represented by non-relapse mortality, while leukemia recurrence affected outcome of a lower number of children. Although the outcome of children experiencing grade III-IV aGvHD is improving over time, strategies aimed at preventing this immune-mediated complication and at optimizing its treatment are desirable. DisclosuresBader:Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

Efficacy of Reduced-Intensity Allogeneic Stem Cell Transplant after Brentuximab Vedotin in Patients with Hodgkin Lymphoma Relapsed after Autologous Transplant

Purpose: The prognosis of patients with Hodgkin lymphoma (HL) who relapse following autologous stem cell transplantation (ASCT) is generally poor, because salvage chemo-radiotherapy is able to produce only short-lasting remissions. In a previous study on a large patients’ population (Sarina B et al, Blood 2010) was clearly demonstrated that the availability of a donor could significantly improve survival outcomes after allogeneic transplant, in particular for the subset of patients who reach a status of pre-transplant complete remission; however the application of this procedure is actually limited by a difficulty to obtain an objective response before alloSCT. It was recently shown that Brentuximab vedotin, a new generation antibody-drug conjugate, is able to induce nearly 30% of complete remission in HL patients relapsing after autologous transplant; therefore this agent could effectively work in relapses after ASCT as a platform to allow a better disease control in order to improve the outcome of the allografting procedure.Aims: Aim of this study was to retrospectively investigate if brentuximab vedotin administered as a salvage therapy in HL patients relapsing after ASCT could improve the efficacy of a subsequent reduced-intensity allogeneic transplant.Methods: Between August 2011 and September 2013, 11 patients underwent to allo-SCT at four hematologic Divisions of Northern Italy for HL relapse after ASCT, after brentuximab vedotin administered as a bridge to the allografting procedure. Median age was 32 years (range 21-61) and median number of prior regimens was 5, including ASCT. Patients received a median of 6 cycles (range 4-7) of brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion; median time between the last dose of brentuximab vedotin and the allo-SCT was 1 month (range 1-5 months). No patient experienced progression during treatment with brentuximab vedotin (4 complete remissions and 7 partial remission/stable disease). All but one patients did not have a HLA identical sibling, so they required a matched unrelated (6 patients), haploidentical donor (3 patients) or cord blood (1 patient); peripheral stem cells were the source in patients with HLA identical sibling or unrelated, whereas bone marrow was used in the haplo setting. Reduced-intensity was the conditioning regimen performed in all patients. Post transplant cyclophosphamide plus mycophenolate mofetil/tacrolimus was the graft-versus-host disease (GVHD) prophylaxis of the haplo setting, while Metotrexate/cyclosporine was administered in the other patients. Patients were monitored for engraftment and infectious complications per institutional standards; survival outcomes were defined according to the European Blood and Marrow Transplantation (EBMT) criteria for survival analysis.Results: One patient had primary graft failure with autologous reconstitution; she was a patient with a high body-mass index, in whom the drug’s doses of the conditioning regimen were underestimated in order to avoid excessive toxicity. All the other patients engrafted; median time to neutrophil recovery was 20 days (range 15-26). At a median follow-up of 12 months, the 2-year progression free survival was 51%, 2-year Overall Survival was 61%. There were 2 toxic deaths, one for EBV reactivation and one for leuko-encefalopathy disease, resulting in a 2-year non-relapse mortality of 18%.Conclusions: These data suggest that brentuximab vedotin represents a promising salvage therapy in HL patients relapsed after ASCT. Despite the bias concerning the differences in source of stem cells and pre-transplant conditioning regimens, we showed that brentuximab could be administered in patients who are candidates to a RIC allo-SCT, with encouraging survival outcomes. Further clinical trials with larger number of patients and longer follow-up are recommended to confirm the promising role of brentuximab as a bridge to alloSCT. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic transplantation strategies including haploidentical transplantation in sickle cell disease

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy. Despite antenatal counseling and neonatal screening programs implemented in higher income countries, SCD is still associated with multiple morbidities and early mortality. To date, the only curative approach to SCD is hematopoietic stem cell transplantation, but this therapy is not yet established worldwide. The registries of the European Blood and Marrow Transplant (EBMT) and the Centre for International Blood and Marrow Transplant Research (CIBMTR) account, respectively, for 611 and 627 patients receiving transplantations for SCD. Most of these patients were transplanted with grafts from an HLA-identical sibling donor. The main obstacles to increasing the number of transplantations are a lack of awareness on the part of physicians and families, the absence of reliable prognostic factors for severity, and the perceived risk that transplantation complications may outweigh the benefits of early transplantation. Results show that more than 90% of patients having undergone an HLA-identical sibling transplantation after myeloablative conditioning are cured, with very limited complications. Major improvement is expected from the use of new reduced-toxicity conditioning regimens and the use of alternative donors, including unrelated cord blood transplantations and related haploidentical bone marrow or peripheral blood stem cell transplantations.

The Survey on Cellular and Engineered Tissue Therapies in Europe in 2011

Following the coordinated efforts of five established scientific organizations, this report describes the "novel cellular therapy" activity (i.e., cellular treatments excluding hematopoietic stem cells [HSC] for the reconstitution of hematopoiesis) in Europe for the year 2011. Two hundred forty-six teams from 35 countries responded to the cellular therapy survey, 126 teams from 24 countries provided data on 1759 patients using a dedicated survey and 120 teams reported no activity. Indications were musculoskeletal/rheumatological disorders (46%; 99% autologous), cardiovascular disorders (22%; 100% autologous), hematology/oncology, predominantly including the prevention or treatment of graft-versus-host disease (18%; 2% autologous), neurological disorders (2%; 83% autologous), gastrointestinal (1%; 68% autologous), and other indications (12%; 77% autologous). Autologous cells were used predominantly for musculoskeletal/rheumatological (58%) and cardiovascular (27%) disorders, whereas allogeneic cells were used mainly for hematology/oncology (84%). The reported cell types were mesenchymal stem/stromal cells (56%), HSC (23%), chondrocytes (12%), dermal fibroblasts (3%), keratinocytes (2%), and others (4%). In 40% of the grafts, cells were delivered following ex vivo expansion, whereas cells were transduced or sorted, respectively, in 3% and 10% of the reported cases. Cells were delivered intraorgan (42%), intravenously (26%), on a membrane or gel (16%), or using 3D scaffolds (16%). Compared to last year, the number of teams participating in the dedicated survey doubled and, for the first time, all European Group for Blood and Marrow Transplantation teams reporting information on cellular therapies completed the extended questionnaire. The data are compared with those collected since 2008 to identify trends in the field. This year's edition specifically focuses on cardiac cell therapy.

Characterization and Prognostic Impact of Oligoclonal Humoral Response in Patients with Multiple Myeloma After Autologous Stem-Cell Transplantation: Long-Term Results From a Single Institution

Abstract 3948 Background:Multiple myeloma (MM) is characterized by the production of a monoclonal immunoglobulin of constant isotype and light chain restriction due to the clonal proliferation of neoplastic plasma cells. The optimal treatment in patients younger than 65 years includes induction therapy followed by high- dose therapy/autologous stem-cell transplantation (ASCT). On the other hand, the emergence of oligoclonal bands is a benign phenomenon frequently associated with complete remission (CR) after ASCT. The aim of the present study was to investigate the incidence, biological characteristics, duration and prognostic value of the oligoclonal bands in patients with MM who underwent ASCT at our institution in the last 18 years. Methods:Two-hundred and eleven patients underwent melphalan-based ASCT at our institution from March 31st, 1994, to December 27th, 2011. Of these, 199 patients (109M/90F; median age 55 years, range 25 to 70) who achieved at the least a partial response (PR) after ASCT are the basis of this study. Initial baseline demographics, clinical and laboratory data, and information concerning treatment and follow up were collected. No patient was lost to follow-up. The median follow-up for alive patients was 4.7 years (range 4 months to 18 years). A retrospective systematic review of all serum and urine immunofixation (IFE) studies was carried out. An oligoclonal humoral response was defined as the presence of a serum and/or urine IFE monoclonal spike different from the original myeloma protein either in heavy and/or light chains, as well as at IFE migration pattern. Response, relapse, and progression were defined according to European Blood and Marrow Transplantation (EBMT) criteria. Results:Median PFS was 87 out of the 199 patients (43.7%) achieved CR. The median progression-free survival (PFS) and overall survival (OS) after ASCT were 3.2 and 6.6 years, respectively. Oligoclonal bands were observed in 34% of the patients, but with different prevalence according to the use of novel agents vs. conventional chemotherapy (63% vs. 22%; p=0.0001) in induction. This phenomena was almost exclusive of patients in CR compared to other degrees of response (92% vs. 8%; p=0.0001). Five patients with IgA and five with Bence Jones MM were the only ones being in PR and having a very transient coexistence of the original M-protein with IgG oligoclonal bands in serum. The median number of different isotypes accounting for oligoclonal humoral response was 2 (range 1 to 6) and this phenomena lasted for a median of 1.35 years. Serum bands were more frequent (75.4%) than those in urine and the main involved serum heavy-chain was IgG (73%), with almost the same distribution kappa/lambda. Kappa light-chain was the predominant isotype in urine (60%).In the overall series, all the oligoclonal bands disappeared before serological and clinical progression, except in two settings. First, patients (n=6) who progressed with extramedullary disease with soft-tissue plasmacytomas without significant bone marrow or serological involvement, had persistent oligoclonal bands for several months. Second, patients with Bence Jones MM (n=6), showing urine M-protein progression at the time of relapse had also a transient persistence of serum oligoclonal bands.The presence of oligoclonal bands after ASCT resulted in a significantly longer PFS (p=0.004). This translated in a significantly longer OS in patients with this humoral oligoclonal response (median OS not reached vs. 5.58 years; p=0.003) (Figure 1). An oligoclonal humoral response stable more than one year after ASCT was associated with a significantly longer clinical PFS and OS than those with shorter duration (p=0.008 and p=0.0001, respectively). Of note, the estimated survival of patients with oligoclonal bands lasting for more than one year at 10 years is 70% (Figure 2). In contrast, the PFS ad OS of patients with oligoclonal bands lasting for less than one year were similar to those who never developed this phenomena. Conclusions:The emergence of oligoclonal bands after ASCT is a prognostic factor and it is usually observed in patients in CR. They reflect a robust humoral immune response and consequently an immune system reconstitution. Duration of this humoral response is also associated with a significant survival prolongation. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Combination of the EBMT Score and the HCT-CI Is Not Better Than the HCT-CI Alone in the Prediction of NRM and OS in Patients Undergoing Allogeneic Hematopoietic Transplantation with Reduced-Toxicity Conditioning

AbstractAbstract 1925In recent years, several pre-transplant models have been developed to predict the outcome after hematopoietic cell transplantation (HCT) through the selection of the best candidates and conditioning regimens. Two models are the most popular one each side of the Atlantic: the HCT Comorbidity Index (HCT-CI) and the European Blood and Marrow Transplantation (EBMT) score. Their predictive capacity has been demonstrated in several studies. Since these models are focused on different pre-HCT characteristics (HCT-CI on comorbidities and the EBMT score on more classical risk factors) we hypothesized that the combination of the two could improve their individual predictive capacity.To that end, we retrospectively analyzed pre-HCT characteristics of all consecutive patients receiving a reduced-toxicity allogeneic HCT (allo-HCT) in 4 Spanish centers from 1999–2008. The HCT-CI and the EBMT scores were calculated as originally defined. Patients were then classified according to the HCT-CI in the original categoriesas originally defined and regardingto the EBMT score in two groups according to the median score of the whole cohort. Multivariate analyseis including pre-HCT characteristics were performed using Cox proportional Hazard models and taking into account the competitive risk structure. The predictive capacity of each model was calculated using the c-statistics. Patients were included in the same protocol of reduced-toxicity allo-HCT with fludarabine-based conditioning in combination with melphalan (70–140 mg/m2) or busulfan (8–10 mg/kg). The median follow-up for survivors was 51 months (range 3–123).A total of 442 recipients (80% transplanted from HLA identical siblings) were included. Most frequent diseases were acute leukemia/MDS (n=156, 35%) and non-Hodgkin lymphoma/chronic lymphocytic leukemia (n=125, 28%). The HCT-CI score distribution was: score 0 (n=87, 20%), score 1–2 (n=130, 29%) and score ≥3 (n=225, 51%) while for the EBMT score was 0–2 (n=62, 14%), 3–4 (n=194, 44%) and >4 (n=187, 42%). The probability of 100-day Non-Relapse Mortality (NRM), 4y-NRM and 4y-overall survival (OS) for the whole cohort were 12% (95%CI 11–14), 35% (95%CI 33–38) and 45% (95%CI 48–50), respectively. In the multivariate analysis, the HCT-CI had and impact on 4y-NRM (score 0: HR 1.0; scores 1–2: HR 1.6 [95%CI 0.9–3], p=0.09; scores ≥ 3: HR 2.3 [95%CI 1.3–3.8], p=0.003) and 4y-OS (score 0:HR of death 1.0; scores 1–2: HR 1.3 [95%CI 0.8–2], p=0.2; scores >2: HR 1.9 [95%CI 1.3–2.8], p=0.002) while the EBMT score did not (p=0.4 and p=0.5, respectively).Using the two models we classified the patients were classified into 3 groups: patients with low HCT-CI (0–2) and low EBMT score (<4) (Group 1), patients with high HCT-CI or high EBMT score (Group 2) and patients with both high HCT-CI and EBMT score (Group 3). The HR for 4y-NRM were: group 1 (HR 1.0), group 2 (HR 1.1 [95%CI 0.6–2], p=0.7), group 3 (HR 1.8 [95%CI 1–3], p=0.04) and for 4y-OS was: group 1 (HR 1.0), group 2 (HR 1 [95%CI 0.6–1.5], p=0.8), group 3 (HR 1.6 [95%CI 1–2.3], p=0.04).Regarding the predictive capacity of each model, the HCT-CI alone captured 58% (c- 95%CI: 53–62), the EBMT score 54% (c- 95%CI: 51–58) while the combination of the two models captured 57% (c- 95%CI: 53–61) of the patients.Finally, the impact of EBMT score was explored in each HCT-CI group. In patients with HCT-CI scores of 0 and 1–2, the EBMT score did not have an impact on NRM and OS. In the cohort of high HCT-CI score (>2), patients with low EBMT score showed a trend to lower risk of NRM (HR 0.6 [95%CI 0.3–1], p=0.08) with a similar risk as for patients with HCT-CI of 1–2 (Figure 1).In conclusion, high HCT-CI scores but not high EBMT scores are associated with worse outcome in patients undergoing reduced toxicity allo-HCT. The addition of the EBMT score contributes little to the HCT-CI, except maybe for patients with more and severe comorbidities. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Pattern of Relapse and Progression After Autologous Stem-Cell Transplantation As Upfront Treatment for Multiple Myeloma

AbstractAbstract 3987 Background:Autologous stem cell transplantation (ASCT) is the gold standard as first-line treatment in young patients with multiple myeloma (MM). Prognostic factors have been usually related to patient characteristic and disease stage. Few investigations on the pattern of relapse or progression after ASCT have been addressed. The differentiation of serological or asymptomatic progression versus clinical relapse requiring treatment is also an important issue. The aim of this study was to investigate the characteristics at the time of relapse or progression in patients with MM who received ASCT as part of a first-line treatment. Patients and Methods:Two-hundred and eleven patients underwent melphalan-based ASCT at our institution during the last 18 years. Of these, 170 patients (87M/83F; median age 56 years, range 25 to 70) who achieved at the least a minimal response (PR) after no more of two induction lines before ASCT are the basis of this study. Initial baseline demographics, clinical and laboratory data at relapse or progression, and information concerning treatment and follow up were collected. The M-protein heavy-chain isotype was IgG (57%), IgA (23%), light chain only (14%) and others (3.5%). Only 2.5% were oligosecretory MM. Extramedullary plasmacytomas (EMP) were observed in 37 out of 170 patients (22%) at diagnosis. The ISS stage was I (45.3%), II (26.5%), III (18.8%) and unknown (9.5%). 12.6% of the patients had a serum creatinine level ≥2 mg/dL and 16.2% had hypercalcemia. The median follow-up for alive patients was 3.9 years (range 4 months to 18 years). Response, relapse, and progression were defined according to European Blood and Marrow Transplantation (EBMT) criteria. Results:Median PFS was 3.3 years (CI 95% 2.7 to 3.9 years) and the median OS of 6.8 years (CI 95% 3.9 to 9.6 years). 47.7% of the patients achieved a complete remission (CR). As of December 2011, 93 patients (54.7%) had relapsed or progressed after ASCT. 37 out of the 93 patients (40%) had relapsed from CR, while the remaining 60% had progressed from PR. A serological or asymptomatic relapse/progression was as frequent as a symptomatic one (49.5% vs. 50.5%, respectively), the latter requiring immediate treatment in the median of a month. Patients with serological relapse/progression had a significantly longer OS than those requiring immediate treatment (p=0.002)(Figure). The main clinical reasons to start myeloma therapy were anemia (43%), new bone lytic lesions (36%), EMP (23.7%), bone pain (14.4%), renal insufficiency (12.2%) and/or hypercalcemia (9%).22 of the 93 patients (24%) relapsed/progressing patients had EMP at the time of progression. In three of them, the extramedullary involvement was the only criteria of progression. The presence of EMP at diagnosis was significantly associated with extramedullary disease at relapse (p=0.001). In fact, 12 out of the 22 patients (54.5%) with EMP at relapse had also EMP at the time of diagnosis.Median time between serological relapse or progression and treatment was of only 5.6 months (range 0 to 5.6 years). However, in 12 out of 46 patients (26%) with serological relapse/progression, treatment was not initiated within first two years. Finally, time to next treatment was significantly longer in patients relapsing from CR (median 2.85 years; CI 95% 2.1 to 3.6) vs. those progressing from PR (median 1.65 years; CI 95% 1.1 to 2.2) (p=0.017). Conclusion:After ASCT, serological or asymptomatic relapse/progression is observed in about one half of the patients. The treatment-free interval in these patients is longer in patients relapsing from CR than in those progressing from PR. Patients with symptomatic relapse/progression have shorter OS. Extramedullary involvement is frequent, being the highest risk in patients with EMP at diagnosis. Finally, relapse/progression with extramedullary disease only is rare. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Are Colony Stimulating Factors (G-CSF) Still Needed in Treatment of Severe Aplastic Anemia in Children?

AbstractAbstract 4400 Objective.Allogenic bone marrow transplantation is the first choice in children with severe acquired aplastic anemia (SAA), but if there is no matched sibling donor, the immunosuppressive therapy (IST) which consists of ATG combined with cyclosporine A, steroids and/or colony stimulating factors (G-CSF), is the best way of treatment.In last two decades there was a trend to add G-CSF to combination of ATG and CSA. Nowadays there is much uncertainty about this practice. There are discussion whether it really reduces early infectious mortality. There are suggestions too, that long term using of G-CSF can play role in developing clonal disorders. Aim.The aim of this study was to assess the influence of period of using colony stimulating factors for the event free survival (EFS), and progression free survival (PFS), infectious side effects, clonality and relapses in patients with SAA. Methods.The group of 55 children with SAA and vSAA (23 girls and 32 boys,) were retrospectively analyzed. The median age of children was 10 years (range 6mth-17,5 years). IST (Thymoglobuline, steroids, CSA, and/or GSF-CS) was given according to the protocol of The European Blood and Marrow Transplant (EBMT) Severe Aplastic Anemia Working Party.G-CSF was administered at the dose of 5μg/kg/mc, in 52 patients. The median period of administration was 32 days (range 0–187 days)The response to the treatment was assessed on 84, 112,180 and 360 day. Relative risk test and Kaplan–Meier estimator, the univariate analysis and multivariate Cox regression models, test were used to estimate the influence of the period of G-CSF therapy for EFS, PFS, relapse free survival, clonality, toxicity and other side effects in children with aplastic anemia Results.The 2- year probability of event free survival (EFS) was 71,52%. The 5 and 10 –year EFS was 57,7%. Progression free survival (PFS) was 66,53%, at 2 years and 59,13% at 5- and 10 years. The relapse rate was 1,81%. The 2-year probability of not having relapse was 87,68%. Relapse free survival was 75,16% at 5 and 10 years. There was 15 deaths (27,27%), 5 early and 10 late deaths. Infections were the main causes of death. There was one transformation to paroxysmal nocturnal haemoglobinuria (PNH) and no transformation to MDS or AML. There was no significant correlation between EFS, PFS and the duration of G-CSF treatment (p > 0,05 log rank). There was tendency for longer PFS and EFS in patient who had G-CSF administered for shorter period. Relative risk (RR) for patients who didn’t receive G-CSF was connected with 28% lower infection rate. RR for children receivingG-CSF for 1–10 days was 0,55.No infectious episodes were observed in children who were treated with G-CSF for 11 – 21 days. RR for patients treated from 21 to 28 day was 1,71. Patients who were given G-CSF for more than 28 days had RR=1,15. During the G-CSF therapy we observed muscular pains, and capillary leak syndrome, but these side effects didn’t influence survival (p>0,05 log-rank) Conclusions.The duration of G-CSF therapy has no impact on the survival (EFS, PFS), but it is a significant factor concerning infection rate. Colony stimulating factor shouldn't be routinely used. Period of administration should be as short as possible. Disclosures:No relevant conflicts of interest to declare.

Impact of HLA-DPB1 Haplotypes on Outcome of 10/10 Matched Unrelated Hematopoietic Stem Cell Donor Transplants Depends on MHC-Linked Microsatellite Polymorphisms

Hematopoietic stem cell transplantation (HSCT) with HLA-A, -B, -C, -DRB1, -DQB1 allele matched (10 of 10) unrelated donors is still associated with a significant rate of posttransplantation complications. In order to disclose additional immunogenetic factors, we analyzed the impact of HLA-DPB1 disparities and major histocompatibility complex (MHC)-resident microsatellite polymorphisms in 246 HLA 10 of 10 matched HSCT patients. First we showed that patients with more frequent/conserved HLA haplotypes had a higher 5-year survival (55% ± 18% versus 39% ± 18%, P = .021). In addition, DPB1 incompatibilities and 3 microsatellite alleles were associated with outcome. In a Cox regression model adjusting for European Blood and Marrow Transplant (EBMT) risk score, T cell depletion, and year of treatment, HSCT with a tumor necrosis factor d (TNFd) 4/d5-positive donor was associated with increased mortality (hazard ratio [HR] = 2.03; confidence interval [CI] 1.25-3.31; P = .004), whereas the D6S510-184 allele was protective (HR = 0.44; CI 0.22-0.87; P = .018). The 2 MHC-linked genetic donor factors, DPB1 mismatch (MM), and TNFd4/d5-positivity, acted in synergy with the EBMT risk score with an always lower survival (HR = 2.97; CI 1.27-6.92; P = .012). These data show that multiple MHC-linked genetic donor factors impact on outcome after unrelated donor HSCT. Their additive and potentially divergent effects could explain previous discrepant results, particularly with respect to the role of HLA-DPB1 disparities. We conclude that HLA-DPB1 typing combined with a simple TNFd microsatellite genotyping assay may significantly help in pretransplantation risk assessment for graft-versus-host disease and mortality, particularly for patients with several potential 10 of 10 matched donors.

The Survey on Cellular and Engineered Tissue Therapies in Europe in 2009

Thanks to the coordinated efforts of four major scientific organizations, this report describes the "novel cellular therapy" activity in Europe for the year 2009. Fifty teams from 22 countries reported data on 814 patients using a dedicated survey, which were combined to additional 328 records reported by 55 teams to the standard European Blood and Marrow Transplantation (EBMT) database. Indications were cardiovascular (37%; 64% autologous), graft-vs.-host disease (27%; 7% autologous), musculoskeletal (17%; 98% autologous), epithelial/parenchymal (8%; 73% autologous), autoimmune (9%; 84% autologous), or neurological diseases (3%; 50% autologous). Autologous cells were used predominantly for cardiovascular (42%) and musculoskeletal (30%) disorders, whereas allogeneic cells were used mainly for graft-vs.-host disease (58%) and cardiovascular (30%) indications. Reported cell types were mesenchymal stem/stromal cells (MSC) (46%), hematopoietic stem cells (27%), chondrocytes (7%), keratinocytes (5%), dermal fibroblast (13%), and others (2%). In 59% of the grafts, cells were delivered after expansion; in 2% of the cases, cells were transduced. Cells were delivered intraorgan (46%), on a membrane or gel (29%), intravenously (16%) or using 3D scaffolds (8%). As compared to last year, the number of teams adopting the dedicated survey was 1.7-fold higher, and, with few exceptions, the collected data confirmed the captured trends. This year's edition specifically describes and discusses the use of MSC for the treatment of autoimmune diseases, due to the scientific, clinical, and economical implications of this topic.

An Improved Bicistronic CD20/tCD34 Vector for Efficient Purification and In Vivo Depletion of Gene-Modified T Cells for Adoptive Immunotherapy

T-cell-based adoptive immunotherapy is widely used to treat graft rejection and relapse after stem cell transplantation (SCT). However, this approach is hampered by a high risk of life-threatening graft-versus-host-disease (GvHD). Clinical trials have demonstrated the value of suicide genes to modify T cells for the effective control of GvHD. Herewith, we show that the combination of a codon-optimized B-cell antigen (CD20op) with a selection marker based on a cytoplasmic truncated version of the human stem cell antigen CD34 (tCD34) allows the generation of highly enriched gene-modified T cells. We demonstrate coordinate co-expression of both transgenes and high expression of CD20op resulting in an increased susceptibility to Rituximab (RTX)-induced cell death. In addition, T cells partially retained their alloreactive potential and their CD4/CD8 ratio after transduction and expansion. Long-lasting transgene expression was sustained in vivo after adoptive transfer into Rag-1(-/-) mice. Moreover, gene-modified T cells were quickly and efficiently depleted from peripheral blood (PB) and secondary lymphoid organs of transplanted animals after RTX treatment. These results warrant further steps toward a clinical application of CD20op as a suicide gene for adoptive immunotherapy.

Targeted Agents for Chronic Myelogenous Leukemia: Will That Be the End of Allogeneic Bone Marrow Transplantation for That Disease?

Although the drug imatinib has been accepted as the treatment of choice for chronic myelogenous leukemia (CML) in chronic phase (CP) throughout the Western world, allogeneic stem cell transplantation (allo-SCT) continues to remain a widely practiced first-line treatment in countries with limited health care budgets. The rationale is not scientific, but largely economically based. We analyzed a cohort of 46 CML patients who participated in a graft-versus-host disease (GVHD) prophylaxis clinical trial and underwent related HLA-matched allogeneic peripheral blood stem cell transplantation. The median time of follow-up in surviving patients was 43 months (range: 4-89 months). Risk stratification of the population was done by European Blood and Marrow Transplant (EBMT) criteria. The estimated probabilities of overall survival (OS) and leukemia-free survival (LFS) at 3 years in low EBMT risk score (0-2) patients were both 91%, respectively. We conclude that in countries with restricted access to imatinib, allo-SCT should be considered early on as front-line therapy. Continued research support for bone marrow transplantation will be needed to make a global impact on this disease.

Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria: An on Going Joint Study of the AAWP EBMT Group and the French Society of Hematology

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells. The disease is diagnosed with hemolytic anemia, marrow failure or episodes of venous thrombosis. Stem cell transplantation (SCT) is the only curative treatment. Until now, there are few reports of SCT in PNH and all but one includes small numbers of patients (Saso R et al, British Journal of Haematology, 1999).Aim: To evaluate the outcome and survival risk factors of PNH patients after SCT according to clinical status of PNH at time of transplantation, and to perform a comparative analysis with a matched cohort of PNH patients without transplantation.Methods: We analyzed the outcome of PNH patients who underwent SCT in Europe through the European Blood and Marrow Transplant (EBMT) Group Promise registry. An additional questionnaire was sent to all centers on PNH specific history and classification. One hundred and six hematological centers were contacted through the EBMT group. Non-transplanted PNH patients were previously reported to the French Society of Hematology registry (Peffault de Latour R et al, Blood 2008). Both populations will be matched according to the date of PNH complications known to be related to bad outcome (thrombosis, aplastic anemia and/or malignant disease).Results: Between September 1978 and April 2007, 268 PNH patients were reported to the EBMT registry. Among those patients, 141 were updated (74 male, 52%) for the present study from 42 hematological centers. The 3 main indications for SCT were aplastic anemia (n=86, 61%), severe recurrent hemolytic crisis (n=43, 30% and thrombosis (n=31, 30%). Concerning disease subcategories recently described (Parker C et al, Blood 2005) 75 patients were transplanted because of PNH in the setting of another specified bone marrow disorder (54%) and 62 patients because of classical PNH (hemolysis without marrow failure, 45%). At time of SCT, the median age of the population was 30 years (IQR 23 to 36). The median interval from diagnosis of PNH to the time of SCT was 21 months (IQR 7 to 69). Eighty-nine patients were transplanted from HLA-identical siblings (64%). The source of stem cells was mostly bone marrow (n=95, 68%). The 2 main conditioning regimens consisted in Cyclophosphamide with Antihymoglobulin or Busulfan. The graft versus host disease (GvHD) prophylaxis associate ciclosporine with or without methotrexate in 102 patients (72%). During evolution, 9 patients did not engraft (6%). Acute GvHD of grade II or more developed in 35 patients (Grade III–IV, n=12). Chronic GvHD developed in 45 (limited, n=26; extensive, n=19). With a median follow-up (±SE) of 62.5 months (±6.2), 39 patients died. The 5-year survival rate was 70% (±4.2%). The main causes of death were infections (n=19), GvHD (n=9) and Hemorrhage (n=4). None of the variables examined for associations with transplant outcome were statistically significant predictors of survival including: age, interval from diagnosis to transplant, year of transplant, stem cell source, donor type, HLA-matching, indications for SCT and PNH subcategories. The non transplanted PNH population includes 401 patients, diagnosed in France from 1950 to 2005. The median follow-up (±SE) is 123.2 months (±9.8). The 10-year survival rate was 67.8% (±4.6%).Conclusions: This study confirms on a large cohort of PNH patients that SCT using related or unrelated donor is a valuable curative option for PNH complications. Nevertheless, no survival associated risk factor was identified. Due to the reduced number of PNH SCT patients, the on-going matched-control analysis with non transplanted PNH patients is the only way to access the potential benefit of SCT in case of PNH complications.