Elena Guggiari

Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients’ bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II–IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus–mycophenolate–ATG-F–rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Priming of hematopoietic progenitor cells by plerixafor and filgrastim in children with previous failure of mobilization with chemotherapy and/or cytokine treatment.

Plerixafor has been recently approved by the European Medicines Agency for adult patients who have failed other mobilization strategies. Experience in children, however, is extremely limited. We describe the experience of the use of this drug in 8 children under a compassionate-use program in 3 Italian and 2 Spanish centers. Plerixafor was generally well tolerated; only 2 of 8 children reported adverse effects, and these were mild in intensity. Peripheral blood progenitor cell priming was improved with plerixafor in 6 of 8 patients. In the remaining 2 patients, the target CD34+ cell count was below the target of 2×106 cells/kg, although in these patients cell counts before collection were good enough for leukapheresis. Plerixafor, therefore seems to be safe and effective for peripheral blood progenitor cell mobilization in children. Adverse events were comparable with those described with filgrastim alone.

Treosulfan based reduced toxicity conditioning followed by allogeneic stem cell transplantation in patients with myelofibrosis

Allogeneic transplantation is the only potentially curative strategy for myelofibrosis, even in the era of new drugs that so far only mitigate symptoms. The choice to proceed to allogeneic transplantation is based on several variables including age, disease phase, degree of splenomegaly, donor availability, comorbidities and iron overload. These factors, along with conditioning regimen and time to transplantation, may influence the outcome of ASCT. We report 14 patients affected by myelofibrosis with a median age of 57 years (range, 41–76) receiving a treosulfan‐fludarabine based reduced toxicity conditioning. Patients (pts) received a stem cell transplantation from an HLA identical (n = 10) or matched unrelated donor (n = 4). All pts had a complete myeloablation followed by engraftment and in 12 out of 13 evaluated pts donor chimerism was 100% at 1 month. In most cases a reduction of splenomegaly and a reduction (or resolution) of bone marrow fibrosis was observed. After a median follow‐up of 39 months (range, 3–106), the 3‐year probability of overall survival and disease free survival was 54 +/− 14% and 46 +/− 14%, respectively. The cumulative incidence of non‐relapse mortality at 2 years was 39 +/− 15%. Causes of non‐relapse mortality were: infection (n = 2), GvHD (n = 2) and haemorrhage (n = 1).