Benefits and risks of clofarabine in adult acute lymphoblastic leukemia investigated in depth by multi-state modeling

Background: We recently reported results of the prospective, open-label HOVON-100 trial in 334 adult patients with acute lymphoblastic leukemia (ALL) randomized to first-line treatment with or without clofarabine (CLO). No improvement of event-free survival (EFS) was observed, while a higher proportion of patients receiving CLO obtained minimal residual disease (MRD) negativity. Aim: In order to investigate the effects of CLO in more depth, two multi-state models were developed to identify why CLO did not show a long-term survival benefit despite more MRD-negativity. Methods: The first model evaluated the effect of CLO on going off-protocol (not due to refractory disease/relapse, completion or death) as a proxy of severe treatment-related toxicity, while the second model evaluated the effect of CLO on obtaining MRD negativity. The subsequent impact of these intermediate events on death or relapsed/refractory disease was assessed in both models. Results: Overall, patients receiving CLO went off-protocol more frequently than control patients (35/168 [21%] vs. 18/166 [11%], p = 0.019; HR 2.00 [1.13–3.52], p = 0.02), especially during maintenance (13/44 [30%] vs. 6/56 [11%]; HR 2.85 [95%CI 1.08–7.50], p = 0.035). Going off-protocol was, however, not associated with more relapse or death. Patients in the CLO arm showed a trend towards an increased rate of MRD-negativity compared with control patients (HR MRD-negativity: 1.35 [0.95–1.91], p = 0.10), which did not translate into a significant survival benefit. Conclusion: We conclude that the intermediate states, i.e., going off-protocol and MRD-negativity, were affected by adding CLO, but these transitions were not associated with subsequent survival estimates, suggesting relatively modest antileukemic activity in ALL.</p

Alpha beta T-cell graft depletion for allogeneic HSCT in adults with hematological malignancies

We conducted a multicenter prospective single-arm phase 1/2 study that assesses the outcome of alpha beta T-cell depleted allogeneic hematopoietic stem cell transplantation (allo-HSCT) of peripheral blood derived stem cells from matched related, or unrelated donors (10/10 and 9/10) in adults, with the incidence of acute graft-versus-host disease (aGVHD) as the primary end point at day 100. Thirty-five adults (median age, 59; range, 19-69 years) were enrolled. Conditioning consisted of antithymocyte globulin, busulfan, and fludarabine, followed by 28 days of mycophenolic acid after allo-HSCT. The minimal follow-up time was 24 months. The median number of infused CD34(+) cells and alpha beta T cells were 6.1 x 10(6) and 16.3 x 10(3) cells per kg, respectively. The cumulative incidence (CI) of aGVHD grades 2-4 and 3-4 at day 100 was 26% and 14%. One secondary graft failure was observed. A prophylactic donor lymphocyte infusion (DLI) (1 x 10(5) CD3(+) T cells per kg) was administered to 54% of the subjects, resulting in a CI of aGVHD grades 2-4 and 3-4 to 37% and 17% at 2 years. Immune monitoring revealed an early reconstitution of natural killer (NK) and gamma delta T cells. Cytomegalovirus reactivation associated with expansion of memory-like NK cells. The CI of relapse was 29%, and the nonrelapse mortality 32% at 2 years. The 2-year CI of chronic GVHD (cGVHD) was 23%, of which 17% was moderate. We conclude that only 26% of patients developed aGVHD 2-4 after alpha beta T-cell-depleted allo-HSCT within 100 days and was associated with a low incidence of cGVHD after 2 years. This trial was registered at www.trialregister.nl as #NL4767.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Local Authority planning provision for Event Management in Ireland: A Socio-Cultural Perspective

The increasing popularity of the event sector in Ireland has resulted in many community events being developed and marketed to international and domestic tourists alike. This growth has had an effect on host communities in a positive and negative manner. This paper assesses the current levels of Local Authority socio-cultural planning provision and guidelines for event management in Ireland. To achieve this, a content analysis approach was used to illustrate which Local Authorities in the Republic of Ireland employed socio-cultural tools and indicators for event management. Accordingly, analysis revealed a lack of Local Authority socio-cultural planning guidelines or policies for event management. However, this offers and opportunity to be improved by implementing and applying best practice indicators in socio-cultural policies and guidelines for event management in Ireland

Colon-interposition as Replacement for the Esophagus. A Follow-up Study

The longterm results of the use of colon-interposition as a substitution for the esophagus have been studied. Colon-interposition was carried out in eleven patients. There was one operative death. A second child died of an unknown cause nine years and eight months after operation. Nine patients could be studied from sixteen years and nine months to thirteen months after the operation. In six patients a satisfactory result has been achieved. One child is staying in a psychiatric infirmary. Feeding problems due to recurrent fistulae have led to growth retardation in another patient, while a third patient has regurgitation symptoms. A study of the case histories gives insight into the many early and late complications which occur in this operative procedure. The colon-interposition is a complicated procedure and should only be carried out in centers for pediatric surgery, because of its specific indication, its technique and the occurrence of complications afterwards. The development of alternative, less complicated, methods leaves a restricted indication for colon-interposition