Key Points• A double-unit strategy does not decrease transplantation failure risk when a single unit of cord blood with adequate cell dose is available.• Alloreactivity may be enhanced by double-unit cord blood transplantation.Transplantation of 2 unrelated cord blood (UCB) units instead of 1 has been proposed to increase the cell dose. We report a prospective randomized study, designed to compare single-vs double-UCB transplantation in children and young adults with acute leukemia in remission or myelodysplasia. Eligible patients had at least two 4-6 HLA-identical UCBs with >3 3 10 7 nucleated cells/kg for the first and >1.5 3 10 7 for the second. The primary end point was the 2-year cumulative incidence of transplantation strategy failure, a composite end point including transplant-related mortality (TRM), engraftment failure, and autologous recovery. Randomized patients who did not proceed to transplantation due to refractory disease were considered transplantation failures. A total of 151 patients were randomized and included in the intent-to-treat analysis; 137 were transplanted. Double-UCB transplantation did not decrease transplantation strategy failure (23.4% 6 4.9% vs 14.9% 6 4.2%). Two-year posttransplant survival, disease-free survival, and TRM were 68.8% 6 6.0%, 67.6% 6 6.0%, and 5.9% 6 2.9% after single-unit transplantation compared with 74.8% 6 5.5%, 68.1% 6 6.0%, and 11.6% 6 3.9% after double-unit transplantation. The final relapse risk did not significantly differ, but relapses were delayed after double-unit transplantation. Overall incidences of graft-versus-host disease (GVHD) were similar, but chronic GVHD was more frequently extensive after double-UCB transplantation (31.9% 6 5.7% vs 14.7% 6 4.3%, P 5 .02). In an exploratory subgroup analysis, we found a significantly lower relapse risk after double-unit transplantation in patients receiving total body irradiation without antithymocyte globulin (ATG), whereas the relapse risk was similar in the group treated with busulfan, cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell dose remains the standard of care and leads to low TRM. Double-unit transplantation should be reserved for patients who lack such units. This trial was registered at www.clinicaltrials.gov as #NCT01067300. (Blood. 2016;127(26):3450-3457)

Highly immunocompromised pediatric and adult hematopoietic cell transplant (HCT) recipients frequently experience respiratory infections caused by viruses that are less virulent in immunocompetent individuals. Most of these infections, with the exception of rhinovirus as well as adenovirus and parainfluenza virus in tropical areas, are seasonal variable and occur before and after HCT. Infectious disease management includes sampling of respiratory specimens from nasopharyngeal washes or swabs as well as sputum and tracheal or tracheobronchial lavages. These are subjected to improved diagnostic tools including multiplex PCR assays that are routinely used allowing for expedient detection of all respiratory viruses. Disease progression along with high mortality is frequently associated with respiratory syncytial virus, parainfluenza virus, influenza virus, and metapneumovirus infections. In this review, we discuss clinical findings and the appropriate use of diagnostic measures. Additionally, we also discuss treatment options and suggest new drug formulations that might prove useful in treating respiratory viral infections. Finally, we shed light on the role of the state of immune reconstitution and on the use of immunosuppressive drugs on the outcome of infection.

Key Points AML cells resistant to cytarabine are more susceptible to NK-mediated cell lysis. c-Myc regulates ULBP1/2/3 expression and interferes with NK cell susceptibility in primary cytarabine resistant AML blasts.

ObjectiveAdenovirus (AdV) infections are potentially life‐threatening for allogeneic hematopoietic stem cell transplant (allo‐HCT) recipients. The AdVance study aimed to evaluate the incidence, management, and outcomes of AdV infections in European allo‐HCT recipients.MethodsAs part of the study, physician surveys were conducted to determine current AdV screening and treatment practices at their center.ResultsAll of the 28 respondents who treat pediatric patients reported routine AdV screening practices, with 93% screening all allo‐HCT recipients and others screening those with transplant‐related risk factors. Nearly all centers take a pre‐emptive approach to AdV treatment in both high‐ (89%) and low‐risk patients (75%). Among the 14 respondents who treat adult patients, 5 (36%) reported routine screening practices and few (21%) screen all allo‐HCT recipients unless risk factors are present. In adults, pre‐emptive AdV treatment is uncommon and quantitative AdV thresholds are rare. Typical treatment for all patients with symptomatic AdV infection is off‐label intravenous cidofovir.ConclusionsOur findings confirm that screening for AdV is more common in pediatric patients. Antiviral treatment is employed in both pediatric and adult patients, although adults are generally treated when AdV disease is diagnosed. The approach to AdV screening and treatment is risk‐based and consistent with clinical guidelines.

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n = 108), chemotherapy followed by second SCT (n = 70), supportive/palliative care (n = 67), combination of chemotherapy and donor lymphocyte infusion (DLI; n = 30), or isolated reinfusion of donor lymphocytes (DLI; n = 13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy = 385 days, second allograft = 391 days, chemotherapy = 174 days, DLI alone = 140 days, palliative care = 43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR) = 0.85, P = 0.53) unlike chemotherapy alone (HR = 1.43 P = 0.04), palliative care (HR = 4.24, P o 0.0001) or isolated DLI (HR = 1,94, P o 0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

SummaryMinimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse.

BackgroundAllogeneic hematopoietic stem cell transplantation (HSCT), the most widely used potentially curable cellular immunotherapeutic approach in the treatment of hematological malignancies, is limited by life-threatening complications: graft versus host disease (GVHD) and infections especially viral infections refractory to antiviral drugs. Adoptive transfer of virus-specific T cells is becoming an alternative treatment for infections following HSCT. We report here the results of a phase I/II multicenter study which includes a series of adenovirus-specific T cell (ADV-VST) infusion either from the HSCT donor or from a third party haploidentical donor for patients transplanted with umbilical cord blood (UCB).MethodsFourteen patients were eligible and 11 patients received infusions of ADV-VST generated by interferon (IFN)-γ-based immunomagnetic isolation from a leukapheresis from their original donor (42.9%) or a third party haploidentical donor (57.1%). One patient resolved ADV infection before infusion, and ADV-VST could not reach release or infusion criteria for two patients. Two patients received cellular immunotherapy alone without antiviral drugs as a pre-emptive treatment.ResultsOne patient with adenovirus infection and ten with adenovirus disease were infused with ADV-VST (mean 5.83 ± 8.23 × 103 CD3+IFN-γ+ cells/kg) up to 9 months after transplantation. The 11 patients showed in vivo expansion of specific T cells up to 60 days post-infusion, associated with adenovirus load clearance in ten of the patients (91%). Neither de novo GVHD nor side effects were observed during the first month post-infusion, but GVHD reactivations occurred in three patients, irrespective of the type of leukapheresis donor. For two of these patients, GVHD reactivation was controlled by immunosuppressive treatment. Four patients died during follow-up, one due to refractory ADV disease.ConclusionsAdoptive transfer of rapidly isolated ADV-VST is an effective therapeutic option for achieving in vivo expansion of specific T cells and clearance of viral load, even as a pre-emptive treatment. Our study highlights that third party haploidentical donors are of great interest for ADV-VST generation in the context of UCB transplantation. (N° Clinical trial.gov: NCT02851576, retrospectively registered).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0469-0) contains supplementary material, which is available to authorized users.

SummaryRelapse after transplantation is a major cause of treatment failure in paediatric acute lymphoblastic leukaemia (ALL). Here, we report the findings of a prospective national study designed to investigate the feasibility of immune intervention in children in first or subsequent remission following myeloablative conditioning. This study included 133 children who received a transplant for ALL between 2005 and 2008. Minimal Residual Disease (MRD) based on T cell receptor/immunoglobulin gene rearrangements was measured on days À30, 30, 90 and 150 post-transplantation. Ciclosporin treatment was rapidly discontinued and donor lymphocyte infusions (DLI) were programmed for patients with a pre-or post-transplant MRD status ≥10 À3. Only nine patients received DLI. Pre-and post-transplant MRD status, and the duration of ciclosporin were independently associated with 5-year overall survival (OS), which was 62Á07% for the whole cohort. OS was substantially higher in patients cleared of MRD than in those with persistent MRD (52Á3% vs. 14Á3%, respectively). Only pre-transplant MRD status (Hazard Ratio 2Á57, P = 0Á04) and duration of ciclosporin treatment (P < 0Á001) were independently associated with relapse. The kinetics of chimerism were not useful for predicting relapse, whereas MRD monitoring up to 90 d post-transplantation was a valuable prognostic tool to guide therapeutic intervention.