Hemopoietic Stem Cell Transplantation Research Articles

Why is development of new treatments necessary for myasthenia gravis? Recent advances in clinical trials

AbstractDespite the availability of an increasing variety of disease‐modifying therapies, the proportion of patients with generalized myasthenia gravis (MG) who achieved the practical treatment goal remained low at approximately 50%‐60% in our latest survey. Therefore, there is a need for further development of new treatment options based on novel mechanisms of action for MG treatment. Eculizumab and ravulizumab are monoclonal antibodies used to prevent complement‐mediated damage at the endplate of neuromuscular junction in MG with acetylcholine receptor (AChR) antibody. Neonatal Fc receptor (FcRn) antibodies including efgartigimod and rozanolixizumab are currently in different stages of clinical trial. The FcRn antibodies would be rational therapeutic agents for decreasing the levels of pathogenic autoantibodies with IgG isotypes, resulting in reduction in muscle‐specific kinase (MuSK) antibody as well as AChR antibody. Rituximab, a CD20+ B‐cell depleting monoclonal antibody, also results in a significant decrease in autoantibody titers in serum. Several studies indicate that rituximab may have the potential to treat MuSK‐MG. Monarsen, an antisense oligonucleotide, may reduce the production of acetylcholinesterase. A phase 2 study showed improvement in quantitative MG scores while on the drug. Several case reports showed the efficacy of autologous hemopoietic stem cell transplantation in patients with severe MG refractory to conventional therapies. This article introduces the new drugs and their latest development and discusses the evidence for thymectomy in relation to the Japanese clinical guidelines for MG.

A prospective study on the epidemiology and clinical significance of viral respiratory infections among pediatric oncology patients

Respiratory infections in oncology are both common and potentially severe. However, there is still a gap in the literature, regarding the epidemiology of viral respiratory infections in children with cancer. We prospectively enrolled 224 patients, from September 2012 to August 2015. The cohort included children with hematologic or solid malignancies receiving chemotherapy, or undergoing hemopoietic stem cell transplantation, outpatients/inpatients exhibiting signs/symptoms of febrile/afebrile upper/lower respiratory infection. Viral infection was diagnosed by detection of ≥1 viruses from a sample at time of enrollment, using the CLART® PneumoVir kit (GENOMICA, Spain). Α detailed questionnaire including demographics and medical history was also completed. Samples were processed in batches, results were communicated as soon as they became available. Children recruited in whom no virus was detected composed the no virus detected group. Viral prevalence was 38.4% in children presenting with respiratory illness. A single virus was found in 30.4%, with RSV being the most frequent. Viral coinfections were detected in 8%. Children with viral infection were more likely to be febrile upon enrollment and to present with lower respiratory signs/symptoms. They had longer duration of illness and they were more likely to receive antibiotics/antifungals. Only 22% of children with influenza received oseltamivir. Mortality was low (2.7%), however, pediatric intensive care unit (PICU) admission and death were correlated with virus detection. In our study mortality was low and PICU admission was related to virus identification. Further research is needed to clarify whether antibiotics in virus-proven infection are of value and underline the importance of oseltamivir’s timely administration in influenza.

Mixed chimerism established by hematopoietic stem cell transplantation is maintained by host and donor T regulatory cells

AbstractTransplantation is an effective treatment of many clinical disorders, but the mechanisms that regulate immunological tolerance are uncertain and remain central to improving patient outcome. Hemopoietic stem cell transplantation (SCT) often establishes “mixed chimerism” in which immune cells from both the donor and patient coexist in vivo in a setting of immunological tolerance. We studied immune function in 69 patients within 2 months following SCT; 37 were fully donor and 32 displayed mixed chimerism. The proportion of T regulatory (Treg) cells was increased during mixed chimerism and comprised equal numbers of donor and host-derived regulatory cells. This was associated with a tolerogenic PD-L1+ profile on dendritic cells. Importantly, effector T cells from patients with mixed chimerism exhibited reduced cytotoxicity against host target cells in vitro, but this was restored following depletion of CD4+ Treg cells. These data show that Treg cells play a major role in sustaining immunological tolerance during mixed chimerism. These insights should help to guide novel interventions to improve clinical transplantation.

Haemopoietic stem cell transplantation is a curative treatment option with minimal transplant-related complications for patients with severe Glanzmann's thrombasthenia

Glanzmann's thrombasthenia is a rare autosomal recessive bleeding disorder of platelet function caused by a qualitative or quantitative defect of the platelet membrane glycoprotein IIb/IIIa. For patients with a severe form the condition haemopoietic stem cell transplantation (HSCT) is the only

GVHD prophylaxis plus ATLG after myeloablative allogeneic haemopoietic peripheral blood stem-cell transplantation from HLA-identical siblings in patients with acute leukaemia in remission: final results of quality of life and long-term outcome analysis of a phase 3 randomised study

We previously showed that human anti-T-lymphocyte globulin (ATLG) plus ciclosporin and methotrexate given to patients with acute leukaemia in remission, having allogeneic haemopoietic stem-cell transplantation with peripheral blood stem cells from an HLA-identical sibling donor after myeloablative conditioning, significantly reduced 2-year chronic graft-versus-host disease (cGVHD) incidence and severity, without increasing disease relapse and infections, and improves cGVHD-free and relapse-free survival (cGRFS). The aim of an extended follow-up study was the assessment of long-term outcomes, which are, in this context, scarcely reported in the literature. We report unpublished data on quality of life (QoL) from the original study and the results of a follow-up extension. In the original open-label study, patients with acute myeloid and lymphoblastic leukaemia in first or subsequent remission, having sibling HLA-identical allogeneic peripheral blood stem-cell transplantation, were randomly assigned (1:1) to receive ATLG plus standard GVHD prophylaxis with ciclosporin and short-term methotrexate (ATLG group) or standard GVHD prophylaxis without ATLG (non-ATLG group). Conditioning regimens were cyclophosphamide 120 mg/kg with either total body irradiation (12 Gy) or busulfan (12·8 mg/kg intravenously or 16 mg/kg orally), with or without etoposide (30-60 mg/kg). Randomisation was stratified according to centre and disease risk. The primary endpoint was cumulative incidence of cGVHD at 2 years. The primary and secondary endpoints, excluding QoL, have been published. QoL, assessed using European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-HDC29 questionnaires, was an unpublished secondary endpoint, which we now report here. A follow-up extension was then done, with the primary endpoint cumulative incidence of cGVHD. Enrolment has been completed for both studies. The original trial (number, NCT00678275) and follow-up extension (number, NCT03042676) are registered at ClinicalTrials.gov. In the original study, from Dec 14, 2006, to Feb 2, 2012, 161 patients were enrolled and 155 were randomly assigned to either the ATLG group (n=83) or to the non-ATLG group (n=72). In the follow-up study, which started on Feb 7, 2017, and was completed on June 30, 2017, 61 patients were included in the ATLG group and 53 were included in the non-ATLG group. Global health status showed a more favourable time course in the ATLG group compared with the non-ATLG group (p=0·02; treatment by visit interaction). ATLG was descriptively superior to non-ATLG at 24 months for physical function (points estimate -14·8 [95% CI -26·4 to -3·1]; p=0·014) and social function (-19·1 [-38·0 to -0·2]; p=0·047), gastrointestinal side-effects (8·8 [2·5-15·1]; p=0·008) and effect on family (13·5 [1·2-25·8]; p=0·032). Extended follow-up (median 5·9 years [IQR 1·7-7·9]) confirmed a lower 5-year cGVHD incidence (30·0% [95% CI 21·4-41·9] vs 69·1% [59·1-80·1]; analysis for entire follow-up, p<0·001), no increase in relapses (35·4% [26·4-47·5] vs 22·5% [14·6-34·7]; p=0·09), improved cGRFS (34·3% [24·2-44·5] vs 13·9% [7·1-22·9]; p=0·005), and fewer patients still in immunosuppression (9·6% vs 28·3%; p=0·017) in the ATLG group compared with the non-ATLG group. 5-year overall survival, relapse-free survival, and non-relapse mortality did not differ significantly between groups. The addition of ATLG to standard GVHD prophylaxis improves the probability of surviving without disease relapse and cGVHD after myeloablative peripheral blood stem-cell transplantation from an HLA-identical sibling donor for patients with acute leukaemia in remission. Further additional benefits are better QoL and shorter immunosuppressive treatment compared with standard GVHD prophylaxis without ATLG. Therefore, in this setting, ATLG plus standard GVHD prophylaxis should be preferred over the standard GVHD prophylaxis alone. Neovii Biotech.

Myeloid-Derived Suppressor Cells in Hematologic Diseases: Promising Biomarkers and Treatment Targets.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that exist at very low numbers in healthy subjects but can expand significantly in malignant, infectious, and chronic inflammatory diseases. These cells are characterized as early-MDSCs, monocytic-MDSCs, and polymorphonuclear-MDSCs and can be studied on the basis of their immunophenotypic characteristics and their functional properties to suppress T-cell activation and proliferation. MDSCs have emerged as important contributors to tumor expansion and chronic inflammation progression by inducing immunosuppressive mechanisms, angiogenesis and drug resistance. Most experimental and clinical studies concerning MDSCs have been mainly focused on solid tumors. In recent years, however, the implication of MDSCs in the immune dysregulation associated with hematologic malignancies, immune-mediated cytopenias and allogeneic hemopoietic stem cell transplantation has been documented and the potential role of these cells as biomarkers and therapeutic targets has started to attract a particular interest in hematology. The elucidation of the molecular and signaling pathways associated with the generation, expansion and function of MDSCs in malignant and immune-mediated hematologic diseases and the clarification of mechanisms related to the circulation and the crosstalk of MDSCs with malignant cells and other components of the immune system are anticipated to lead to novel therapeutic strategies. This review summarizes all available evidence on the implication of MDSCs in hematologic diseases highlighting the challenges and perspectives arising from this novel field of research.

Targeting the niche: depleting haemopoietic stem cells with targeted therapy.

Haemopoietic stem cell transplantation is an expanding procedure worldwide but is associated with significant morbidity and mortality. Depletion of resident haemopoietic stem and progenitor cells (HSPC) is required for both autologous and allogeneic haemopoietic stem cell transplantation. Current conditioning protocols utilise chemotherapy or radiation to effectively reduce HSPC but are toxic in both the short and long term. The initial trials to use monoclonal antibodies to target HSPC were limited with marginal efficacy but platforms including antibody drug conjugates and chimeric antigen receptor T cells have made targeted conditioning strategies achievable. In this review we summarise the work developing targeted conditioning that may replace or reduce alkylating agents and total body irradiation. The prospect of conditioning with significantly reduced toxicity will improve outcomes and open transplantation to patients unable to tolerate current conditioning protocols.

ПУНКЦИОННОЕ ЛЕЧЕНИЕ СИНУСИТОВ В УСЛОВИЯХ ЦИТОПЕНИИ У РЕЦИПИЕНТОВ ТРАНСПЛАНТАЦИИ ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК

Introduction: Sinusitis is one of the most common infectious complications at the stages of hematopoietic stem cell transplantation. Diagnosis and treatment patients whith cytopenia often causes difficulties for otorhinolaryngologists. Objective: To analyze the possibility of puncture of the maxillary sinuses in patients whith cytopenia after hemopoietic stem cells transplantation. Materials and methods. The case histories of 350 patients whith rhinosinusitis, who received treatment at the Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation from January 2017 to June 2018 were analyzed. Of these patients, 41 (11%) (11 – 62 y.o.) underwent puncture of the maxillary sinuses. The control group included 59 immunocompetent patients undergoing puncture treatment for sinusitis. Results: The clinical picture of sinusitis in patients with cytopenia was different from the classical one. In cases of severe anemia (&lt;80 g/l), paleness of the mucous membranes of the nasal cavity prevailed; with extremely severe neutropenia (&lt;0.5 x 109/l), and leukopenia (&lt;1.0 x 109/l) in the vast majority of patients, the nasal discharge was mucopurulent. 10% patients with drug immunosuppression and agranulocytosis have pronounced edema and hyperemia of nasal soft tissues. In 19.5% patients, who underwent puncture, severe thrombocytopenia (&lt;25 x 109/l) was observed. In 3 (7%) patients, significant bleeding was observed after puncture. In punctate we observed Str. Viridans (26.8%), Pseudomonas spp. (14.6%), and Klebsiella pneumonia (12.2%) of cases. Conclusion: Sinusitis with cytopenia is prone to atypical course. Symptoms in these conditions can vary from scanty to pronounced. Puncture of the maxillary sinuses in such patients can be performed according to indications.

Risk of Patients Developing Post-Transplant Lymphoproliferative Disorder within the First Year after an Allogeneic Hemopoietic Stem Cell Transplant, 2011 to 2016: A US Claims Database Analysis

Introduction: Post-transplant lymphoproliferative disorder (PTLD) is a heterogenous disease that can develop after solid organ or allogeneic hemopoietic stem cell transplant (HCT). PTLD after HCT is primarily of the monomorphic subtype and driven by the Epstein-Barr Virus. It is an ultra-rare disease that follows an aggressive clinical course with poor outcomes and for which there is no approved standard treatment. The risk of PTLD after HCT in the current clinical setting is insufficiently quantified, and large-scale data from the US are lacking. The objective of this study was to estimate the incidence of PTLD after allogeneic HCT using a large US claims database.Methods: A retrospective cohort study using the MarketScan Commercial and Medicare Supplemental database was conducted. Patients who received an allogeneic HCT between January 1, 2011 and December 31, 2016 with at least 6 months of continuous enrollment prior to allogeneic HCT were included in the analysis. PTLD cases were identified as having a diagnosis of PTLD (ICD-9 code 238.77 or ICD-10 code D47Z1) or one inpatient or two outpatient claims for preselected, clinically relevant lymphoma codes within 1-year post-transplant. Patients with a clinically relevant lymphoma diagnosis in the 6 months prior to HCT were excluded. The percentage of patients who developed PTLD during the first year after allogeneic HCT was calculated, the average time to PTLD diagnosis was estimated, and patient characteristics at PTLD diagnosis were described.Results: A total of 2,735 eligible patients were included in the analysis; the mean (range) post-transplant follow-up time was 576 (1-2555) days. Overall, 103 patients (3.8%; 95% CI: 3.1%-4.6%) developed PTLD during the first year after allogeneic HCT, and the median (range) time from allogeneic HCT to PTLD diagnosis was 90 (0-364) days. The mean (SD) age at time of first PTLD diagnosis was 46.8 (17.2) years, with 84.5% of patients 18 to < 65 years old, 8.7% of patients < 18 years old, and 6.8% of patients ≥ 65 years old. There was a higher percentage of male versus female PTLD patients: 55.3% versus 44.7%.Conclusions: This analysis of a large-scale US claims database showed that 3.8% (95%CI: 3.1%-4.6%) of post-allogeneic HCT patients had PTLD within the first year after transplant. Most patients impacted by PTLD were younger than 65 (93.2%), and a substantial proportion were pediatric patients (8.7%). Future studies are needed to better understand the disease state and burden of PTLD as well as the unmet medical need for this patient population. DisclosuresBarlev:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Xu:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Fulcher:IBM Watson Health: Employment. Watson:Atara Biotherapeutics, Inc: Employment, Equity Ownership. Sruti:IBM Watson Health: Employment. Sudhindra:Atara Biotherapeutics, Inc: Employment, Equity Ownership.

EARLY Post-Transplant Events , Cost of Admission and Mortality, in Patients Undergoing Allogeneic Transplants from Identical Siblings, Unrelated Donors or Haploidentical Donors

Abstract Background. The outcome of allogeneic hemopoietic stem cell transplantation (HSCT) is measured in terms of graft versus host disease (GvHD), non-relapse mortality (NRM) and survival. Days of Hospital stay and number of re-admissions, are important surrogates of outcome, quality of life, and also of costs, but are usually not reported. Aim of the study . Assess the number of days alive and outside the Hospital (DAOH) , together with the frequency of a new re-admission, in the first 100 days after transplant. Patients. We analyzed 212 patients who received an allogeneic HSCT from matched sibling (SIB) (n=64), unrelated donors (UD) (n=74) and family haploidentical donors (HAPLO) (n=74). Median age was 49 years (19-71), disease phase was in remission in 53%; diagnoses was acute leukemia (66%) , MDS (14%) chronic disorders 20%. DAOH. The median DAOH for SIB, HAPLO and UD grafts was 78, 72 and 66 days (p=0.0001). The median DAOH for SIB patients was significantly longer than for UD patients (p=0.00002) and for HAPLO grafts (p=0.0008); the median DAOH for UD and HAPLO patients were comparable (p=0.4). Donor type was the strongest predictor of DAOH , followed by a Sorror score &gt;2 (p=0.04). Re-admission. Fifty four patients, of 185 discharged, required a re-admission for complications. the first cause for readmission was fever of unknown origin (54%), followed by GvHD (18,5% ) ,cystitis (8%) , relapse (7%) and respiratory problems (7%). The only factor predicting re-admission was advanced disease (p=0.01). Patients who were re-admitted to hospital within 100 days had a significantly higher risk of non relapse mortality (NRM) (25%) as compared to patient non re-admitted (5%) irrespective of the cause for re-admission (p=0.0001). In a multivariate analysis re-admission was the strongest predictor of NRM, with a risk ratio of 10.9 (p=0.0002). Days of admission and cost. The average number of days in hospital within 100 days from transplant, was 37,6 for UD, 35,0 for HAPLO and 25,0 for SIBS (p=0.0002). The average cost of admission within 100 days from HSCT, was €69522 for UD, €64715 for HAPLO and €46225 euros for SIBS. Conclusion. HAPLO transplants with PT-CY and UD transplants , have lower numbers of DAOH, as compared to SIB grafts, which implies longer stay in hospital and greater cost. Re-admission to Hospital within 100 days is predicted by disease phase and has a very strong impact on non relapse mortality. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Excellent Response to Blinatumomab in Children and Young Adults with Refractory B Lineage Acute Lymphoblastic Leukaemia for Persistent MRD or after Debulking Chemotherapy for Higher Disease Burden

Introduction: A recent phase I/II study of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukaemia (B-ALL), found 39-51% achieved complete, often MRD negative, remission after two cycles of therapy. Higher responses were observed in patients with less than 50% bone marrow blasts, compared to greater than 50% (55.6% vs 32.7% (95% CI 30.8-78.5 and 20.3-47.1 respectively)1. Furthermore, an adult study showed complete minimal residual disease (MRD) response rates of 78% when blinatumomab was used to treat MRD-positive ALL in haematological remission 2. Hence response rates (and toxicity) to blinatumomab are highly correlated with pre-treatment disease burden. We present preliminary data showing an excellent response to blinatumomab in children and young adults with resistant B-ALL who had persistent MRD, or after debulking chemotherapy to achieve a partial remission.Methods: Eleven patients were identified through a national survey. The mean age of patients was 10 years (range 0.7-22 years, 3 infants and 1 Down syndrome ALL). All patients had B-lineage ALL which was CD19 positive. None had active CNS disease at the point of receiving blinatumomab. Prior to administration of blinatumomab, all patients either had persistent MRD following several courses of intensive chemotherapy or received debulking chemotherapy for heavier marrow infiltrates. Pre-blinatumomab chemotherapy to which the patients had failed to obtain an adequate MRD response included UKALL 2011 Regimens A or C, UKALL R3, Interfant 06 or NOPHO high risk blocks. Patients received 5-15 µg/m2 of blinatumomab for 1-2 cycles prior to definitive therapy.Results: Pre-blinatumomab, all patients except one were in morphological remission with MRD measurable by PCR (0.003-1%), the remaining patient had 9% marrow disease by morphology. After 1-2 cycles of blinatumomab all patients had negative MRD when measured by flow cytometry and/or by PCR, giving a 100% response rate. This was followed by Haemopoietic stem cell transplant (HSCT) in nine patients and the remaining two are awaiting transplant. Further data on patient characteristics, CNS status, relapse and survival outcome are being collected and will be presented at the meeting.Minimal toxicity was observed; of the seven patients in whom toxicity data were available, three had grade 1 CRS, which resolved spontaneously without interruption of therapy or treatment with corticosteroids or Tocilizumab. One patient reported grade 1 neurotoxicity.This preliminary UK experience demonstrates that excellent MRD response is observed with minimal toxicity in children and young adults who receive blinatumomab for persistent MRD or after debulking chemotherapy. This provided a bridge to transplant in patients who would otherwise not have benefited from the procedure because of persistent MRD. We are planning to extend these observations by undertaking a study of this strategy in first high-risk B-ALL relapse.Stackelberg Av, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Journal of Clinical Oncology. 2016;34(36):4381-4389.Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. DisclosuresGhorashian:Celgene: Other: travel support; Novartis: Honoraria. Marks:Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy. Vora:Amgen: Other: Advisory board; Novartis: Other: Advisory board; Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board.

Co-Administration of 3rdparty Partially HLA Matched Cytomegalovirus Specific T Cells with Initial Antiviral Pharmacotherapy for Post-Transplant Viral Reactivation

▪INTRODUCTION Cytomegalovirus (CMV) infection is common after allogeneic haemopoietic stem cell transplant (HSCT), especially in the first 12 months when the recovering immune system is immature. We are conducting an early phase clinical trial of 3rd party donor-derived, partially HLA matched, virus-specific T cells (VST) for initial reactivation of CMV after HSCT.RESULTS At data cutoff for this analysis (July 15 2018), we had administered 22 infusions of CMV VST to 15 HSCT recipients (age 1-70 years, median 57; male n=9, female n=6) with reactivation of CMV within 7 days of first commencement of antiviral pharmacotherapy. Up to 3 VST infusions were given (1 infusion n=9, 2 n=5 and 3 n=1). Diagnoses include AML/MDS (n=5), ALL (n=2), NHL (n=3), CML, CMML, MDS/MPN, mucopolysaccharidosis type 1 and ARPC1B deficiency (n=1 each). Patients received reduced intensity conditioning (n=10) and myeloablative conditioning (n=5) and were transplanted from matched unrelated donors (n=9), mismatched unrelated donors (n=3), a matched sibling (n=1) and haploidentical donors (n=2). Haploidentical graft recipients received graft versus host disease (GVHD) prophylaxis with post-transplant cyclophosphamide, cyclosporine and mycophenolate mofetil. All other patients with the exception of the sibling graft recipient and two pediatric graft recipients received thymoglobulin. Two pediatric graft recipients received alemtuzumab in vivo and CD34 ex vivo selected stem cells respectively. Eleven patients were CMV D+/R+, 4 patients were D-/R+. Median day of first VST infusion was day 49 post-transplant (range 34-83). There were no significant infusion related reactions. Of the fifteen patients who received treatment for CMV, median maximum CMV copy number prior to first VST infusion was 6088 copies/ml (range 2342 to 53140). 12 patients (80%) achieved a complete virological response (defined as at least one negative PCR test after infusion). The remaining 3 patients achieved a virological PR (at least 50% reduction in CMV copy number); in 2 of these 3 cases CMV fell below the level of assay quantitation but remained detectable. Median time to CR was 21 days (range 9-53) and to PR was 20.5 days (range 12-48). Twelve of the 22 infusions (55%) were followed by complete virological response. Median number of days in hospital after VST infusion was 0 (0-83). Median number of days of CMV antiviral administration was 21 (range 7-72). All but 2 patients had additional non-bacterial pathogens isolated post-transplant (1 n=4, 2 n=5, ≥3 n=4). 3 patients developed acute graft versus host disease, 2 post VST infusion (grades I and II skin), 1 both before (grade IV gut GVHD) and after VST infusion (grade IV gut GVHD) on steroid weaning. One patient has developed mild chronic GVHD affecting mouth and liver. CMV pneumonitis was observed in 1 patient after VST infusion as part of complex lung pathology comprising pulmonary veno-occlusive disease, pulmonary fibrosis and positive lung PCR testing for CMV, EBV and HHV6. 5 patients were censored at post-transplant days 111 (relapse CMML), 122 (secondary graft rejection after CD34 selected transplant), 155 (unmanipulated DLI for falling myeloid chimerism), 160 (relapse ALL) and 275 (ATG for second line therapy of grade IV gut GVHD). At a median follow up of 165 days (42-279) 14 of 15 patients (93%) remain alive (1 death due to relapse). At date of last follow up, 12 patients had ECOG status 0, 1 had ECOG 2 and 2 had ECOG 4.Post VST infusion CMV specific immune reconstitution was observed with a rise in pp65 specific cellular immune response measured by IFN-g elispot (median 152 spot forming unitsx104/L before infusion to median peak of 2710 after infusion; p=0.006; Fig 1). HLA mismatched 3rd party cells were detectable in the peripheral blood in 4 of 9 patients at low levels (mean 0.012%) by a high sensitivity digital PCR chimerism assay up to day 97 post infusion.CONCLUSION Early administration of 3rd party partially HLA matched CMV-specific T-cells in association with standard antiviral treatment is non-toxic and does not induce a high rate of acute GVHD. These preliminary data suggest that this approach is associated with good viral control and performance status in allogeneic transplant recipients. Recruitment of additional patients, longer follow up and ultimately a randomized study will be required to determine whether addition of early cell therapy of this kind adds value to standard antiviral treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Imatinib treatment of paediatric Philadelphia chromosome-positive acute lymphoblastic leukaemia (EsPhALL2010): a prospective, intergroup, open-label, single-arm clinical trial

The EsPhALL2004 randomised trial showed a 10% advantage in disease-free survival for short, discontinuous use of imatinib after induction compared with no use of imatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia receiving Berlin-Frankfurt-Münster chemotherapy and haemopoietic stem-cell transplantation (HSCT). Other contemporary studies showed an advantage from continuous protracted exposure to imatinib, challenging the indications to transplant. The EsPhALL2010 study was designed to assess whether imatinib given from day 15 of induction and continuously throughout chemotherapy led to a different outcome to that obtained in EsPhALL2004, despite decreasing the number of patients having HSCT. This prospective, intergroup, open-label, single-arm clinical trial (EsPhALL2010) was done at 11 study groups across Europe, Chile, and Hong Kong. Patients aged 1-17 years with the translocation t(9;22)(q34;q11) who were recruited into national front-line trials for acute lymphoblastic leukaemia were eligible for this trial. Patients with abnormal renal or hepatic function or an active systemic infection were ineligible. Patients received imatinib 300 mg/m2 continuously from day 15 of induction during chemotherapy. Eligibility to HSCT depended on early morphological response and minimal residual disease. Imatinib was recommended throughout the first year after transplant. The co-primary endpoints were event-free survival and overall survival. All analyses were done in the intention-to-treat population. The trial is registered with the European Clinical Trials Database (EudraCT 2004-001647-30) and with ClinicalTrials.gov (NCT00287105) and is completed. 158 patients were screened for eligibility, of whom 155 were enrolled between Jan 1, 2010, and Dec 31, 2014. 151 (97%) patients achieved first complete remission after induction and four after the consolidation phase, with 102 (66%) patients categorised as good risk and 53 (34%) as poor risk according to EsPhALL risk stratification criteria. 59 (38%) patients had HSCT during their first complete remission. 40 (26%) patients relapsed and 41 (26%) patients died during the study (25 [61%] during complete continuous remission, and 16 [39%] after relapse). The 5-year event-free survival was 57·0% (95% CI 48·5-64·6) and 5-year overall survival was 71·8% (63·5-78·5). 154 serious adverse events were reported in 80 (52%) of 155 patients. The most common toxicity was infection (61 [39%] patients, mostly bacterial); gastrointestinal disorders occurred in ten (6%) patients and osteonecrosis in eight (5%). Serious adverse events occurred mainly during high-risk blocks and delayed intensifications, including 14 fatal events (one in the consolidation phase, six in high-risk blocks, six in first delayed intensification, and one in second delayed intensification). Although HSCT was done in a smaller proportion of patients in EsPhALL2010 than in EsPhALL2004, event-free and overall survival were similar between the two studies. Our data suggest that imatinib given early and continuously with intensive chemotherapy might increase toxicity. Projet Hospitalier de Recherche Clinique-Cancer and Novartis France; Bloodwise and Cancer Research UK; Ministry of Health, Czech Republic.

Impact of T-cell depletion strategies on outcomes following hematopoietic stem cell transplantation for idiopathic aplastic anemia: A study on behalf of the European blood and marrow transplant severe aplastic anemia working party.

We retrospectively analyzed the outcomes of 1837 adults and children with severe aplastic anemia (SAA) who underwent matched sibling donor (MSD) and matched unrelated donor (MUD) hemopoietic stem cell transplantation (HSCT) between 2000 and 2013. Patients were grouped by transplant conditioning containing either anti-thymocyte globulin (ATG) (n = 1283), alemtuzumab (n = 261), or no serotherapy (NS) (n = 293). The risks of chronic GvHD were significantly reduced when ATG or alemtuzumab were compared with NS (P = .021 and .003, respectively). Acute GVHD was significantly reduced in favor of alemtuzumab compared with ATG (P = .012) and NS (P < .001). By multivariate analysis, when compared with ATG, alemtuzumab was associated with a lower risk of developing acute (OR 0.262; 95% CI 0.14-0.47; P < .001) and chronic GVHD (HR 0.58; 95% CI 0.35-0.94; P = .027). OS was significantly better in ATG and alemtuzumab patients compared with NS (P = .010 and .025). Our data shows inclusion of serotherapy in MSD and MUD HSCT for patients with SAA reduces chronic GVHD and provides a survival advantage over patients not receiving serotherapy. Notably, alemtuzumab reduced the risk of acute and chronic GvHD compared with ATG and indicates that alemtuzumab might be the serotherapy of choice for MSD and MUD transplants for SAA.

Construction of nursing quality evaluation index for hematopoietic stem cell transplantation

Objective To establish the index system of nursing quality evaluation for patients with hematopoietic stem cell transplantation. Methods Based on the Donabedian structure-process-result three-dimensional quality management model, the evaluation index system of nursing quality of stem cell transplantation was constructed by combining qualitative and quantitative research of literature inquiry, case review, expert inquiry and analytic hierarchy process. Results Through the second round of expert consultation, the effective recovery rate of the expert questionnaire was 100%, the expert authority coefficient was 0.813, 0.859, and the coordination coefficient was 0.235 and 0.278 respectively (P< 01). Three primary indicators, 14 secondary indicators and 48 tertiary indicators were formed to evaluate the quality of care in stem cell transplantation. The index weight coefficient was established and the consistency test was passed. Conclusion The quality index system of hematopoietic stem cell transplantation nursing is well defined, its weight allocation is reasonable, the index is clear, and it is scientific and operational. Key words: Hemopoietic stem cell transplantation; Quality of care indicators; Hierarchy; Delphi method

Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial

Haemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities. This non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 μmol/min (16K group) or 20 000 μmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m2 for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662. Between April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54-67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0-10) in the 16K group and 6% (0-13) in the 20K group (p=0·65). Infection was the most common grade 3-5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group. Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse. Cancer Center Support Grant (US National Cancer Institute, National Institutes of Health).

Nivolumab therapy for refractory and relapsed Hodgkin’s lymphoma — case report

A case of a 34-year-old male patient was described with increased sweating, itching of the skin without accompanying skin lesions, and a dry cough. Numerous enlarged nodes in the chest and hypodense centres in the spleen were visualised in the CT imaging. Based on lymph node biopsy, Hodgkin’s lymphoma (HL) nodular sclerosis type was diagnosed. After ABVD (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 mg/m2), chemotherapy, and radiotherapy complete remission was achieved. Two months after treatment completion the disease relapsed. Six courses of chemotherapy DHAP (cisplatin 100 mg/m2 on day 1, cytarabine 2000 mg/m2 every 12 hours on day 2, dexamethasone 40 mg on day 1–4) were followed by high-dose chemotherapy BEAM (carmustine 300 mg/m2, etoposide 400–800 mg/m2, cytarabine 800–1600 mg/m2, and melphalan 140 mg/m2) supported with autologous transplantation of haemopoietic stem cells (ASCT). Through numerous relapses of the disease, the patient received many lines of chemotherapy and immunotherapy, including IGEV (ifosfamide 2000 mg/m2 on day 1–4, gemcitabine 800 mg/m2 on day 1–4, vinorelbine 20 mg/m2 on day 1), brentuximab vedotin 1.8 mg/m2 (BV), CNOP (cyclophosphamide 750 mg/m2, mitoxantrone 10 mg/m2, vincristine 1.4 mg/m2, dexamethasone 20 mg), chlorambucil 12 mg daily for 14 days with a seven-day break + prednisone chronically in a dose of 40 mg daily, and TBS (thalidomide 100 mg per day chronically, bendamustine 90 mg/m2 on day 1–2, methylprednisolone 1000 mg/day on day 1–3). We decided to introduce an immunotherapy with nivolumab, the anti-PD1 antibody, achieving a significant clinical response. This case report presents nivolumab as an effective treatment in refractory and relapsed HL.

Bulky primary tibia mantle cell lymphoma achieved complete remission with CHOP and DHAP plus rituximab: A case report.

Mantle cell lymphoma (MCL) is a subtype of B-cell non-Hodgkin lymphoma. Heterogeneous and extensive lymphadenopathy is the most common clinical manifestation. Although skeletal involvement is not uncommon in other types of non-Hodgkin lymphoma, primary bone MCL is rare. The present study reported a case of primary tibia MCL in a 50-year-old male presenting with left tibia pain and a rapidly growing lump. Computed tomography and magnetic resonance imaging scans revealed a progressive lesion in the cortical bone and surrounding soft tissue mass. A positron emission computed tomography scan demonstrated increased glucose metabolism in the middle tibia without involvement of regional lymph nodes. An aspiration biopsy was performed, and pathological examination revealed small-medium sized cells strongly positive for cluster of differentiation (CD)5, CD20 and cyclin D1. Fluorescent in situ hybridization analysis confirmed the presence of immunoglobulin heavy chain/cyclin D1 gene fusion formed by t(11;14) translocation. As a result, primary bone MCL was diagnosed and rituximab-containing chemotherapy was administered. Following complete remission, autologous hemopoietic stem cell transplantation and rituximab maintenance therapy were performed. During the 2-year follow-up period, the patient remained in a good condition without signs of relapse.

Non‐transferrin‐bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload

Non‐transferrin‐bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload

Primary antifungal prophylaxis: decrease of invasive fungal disease incidence and reduction of risk factors in haematological patients in a 5-year retrospective study.

Invasive fungal disease (IFD) is a major cause of morbidity and mortality in patients with haematological malignancies. To evaluate the efficacy and rationality of primary antifungal prophylaxis (PAP) in a 5-year real-life setting and choose an appropriate PAP strategy. Clinical data of patients were retrospectively reviewed and IFD was diagnosed using the revised diagnostic criteria. The efficacy of PAP and the risk factors for IFD, especially the rationality of PAP, were evaluated. Of the 1340 patients enrolled, 749 patients received PAP (55.9%), and IFD occurred in 157 patients: 51 (6.8%) in the PAP group and 106 (17.9%) in the non-PAP group (P = 0.000). The IFD-related mortality was 10.1 and 29.7% in the PAP group and non-PAP group (P = 0.000) respectively. PAP was an independent protective factor for IFD (odds ratio = 0.183, 95% confidence interval: 0.122-0.274, P = 0.000) and could reduce the effect of risk factors, such as allogeneic haemopoietic stem cell transplantation, prolonged neutropenia and corticosteroid. The IFD incidence was not significantly different among different PAP regimens and PAP start time subgroups, and it was lowest (4.2%) when PAP started after a short period of neutropenia (1-10 days). PAP is necessary and efficient to prevent IFD in haematological patients, and the real-life PAP strategy is reasonable. Different drugs can be chosen, and it is better to start PAP as soon as neutropenia begins.