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Martino M.,Hematology and Bone Marrow Transplant Unit | Laszlo D.,Hemato Oncology Unit | Lanza F.,BMT Unit
Expert Opinion on Biological Therapy | Year: 2014

Introduction: Peg-filgrastim (PEG-FIL), a polyethylene glycol-conjugated form of granulocyte colony-stimulating factor (G-CSF), has been introduced in clinical practice and is effective in shortening the time of neutropenia after cytotoxic chemotherapy. G-CSF has emerged as the preferred cytokine for hematopoietic progenitor cells' (HPC) mobilization. Nevertheless, data on the ability of PEG-FIL in this field have been published. Areas covered: We review publications in the field with the goal of providing an overview of this approach. Expert opinion: PEG-FIL may be able to mobilize CD34+ cells in a more timely fashion than G-CSF, with the advantages of only a single-dose administration, an earlier start and a reduction in the number of apheresis procedures. The main controversies concern the dosage of the drug and the optimal dose. In the context of chemo-mobilization, a single dose of 6 mg PEG-FIL seems effective in terms of HPC's mobilization and there is no increase in this effect if the dose is doubled to 12 mg. Steady-state mobilization requires higher doses of PEG-FIL and this approach is not cost-effective when compared with G-CSF. The experiences with PEG-FIL in the healthy donor setting are very limited. © 2014 Informa UK, Ltd.

Chiaretti S.,University of Rome La Sapienza | Zini G.,Catholic University of the Sacred Heart | Bassan R.,Hematology and Bone Marrow Transplant Unit
Mediterranean Journal of Hematology and Infectious Diseases | Year: 2014

Acute lymphoblastic leukemia (ALL) is a disseminated malignancy of B- or T-lymphoblasts which imposes a rapid and accurate diagnostic process to support an optimal risk-oriented therapy and thus increase the curability rate. The need for a precise diagnostic algorithm is underlined by the awareness that both ALL therapy and related success rates may vary greatly between ALL subsets, from standard chemotherapy in patients with standard-risk ALL, to allotransplantation (SCT) and targeted therapy in high-risk patients and cases expressing suitable biological targets, respectively. This review summarizes how best to identify ALL and the most relevant ALL subsets.

Bassan R.,UOC Ematologia | Spinelli O.,Hematology and Bone Marrow Transplant Unit
Current Hematologic Malignancy Reports | Year: 2015

Almost 90 % of children and 50 % of adults with acute lymphoblastic leukemia (ALL) are cured by modern treatment regimens, with significant variations due to several disease- and host-related characteristics. The attainment of an early remission and the avoidance of relapse and treatment-related mortality are the fundamental therapeutic steps. In remission patients, the assessment of the disease response to early intensive therapy through the detection and monitoring of minimal residual disease (MRD) can accurately refine the individual prognosis and is increasingly used to support a risk-oriented treatment strategy. In this way, only the patients with an unfavorable MRD response are preferably selected for allogeneic stem cell transplantation, irrespective of their clinical risk class. This choice spares transplant-related toxicities to MRD responsive cases. Further advancement is expected by integrating the MRD analysis with improved pediatric-type regimens and novel targeting agents for ALL subsets at higher risk of relapse. © 2015, Springer Science+Business Media New York.

Rambaldi A.,Hematology and Bone Marrow Transplant Unit | Biagi E.,University of Milan Bicocca | Bonini C.,San Raffaele Scientific Institute | Biondi A.,University of Milan Bicocca | Introna M.,Hematology and Bone Marrow Transplant Unit
Leukemia | Year: 2015

When treatment fails, the clinical outcome of acute leukemia patients is usually very poor, particularly when failure occurs after transplantation. A second allogeneic stem cell transplant could be envisaged as an effective and feasible salvage option in younger patients having a late relapse and an available donor. Unmanipulated or minimally manipulated donor T cells may also be effective in a minority of patients but the main limit remains the induction of severe graft-versus-host disease. This clinical complication has brought about a huge research effort that led to the development of leukemia-specific T-cell therapy aiming at the direct recognition of leukemia-specific rather than minor histocompatibility antigens. Despite a great scientific interest, the clinical feasibility of such an approach has proven to be quite problematic. To overcome this limitation, more research has moved toward the choice of targeting commonly expressed hematopoietic specific antigens by the genetic modification of unselected T cells. The best example of this is represented by the anti-CD19 chimeric antigen receptor (CD19.CAR) T cells. As a possible alternative to the genetic manipulation of unselected T cells, specific T-cell subpopulations with in vivo favorable homing and long-term survival properties have been genetically modified by CAR molecules. Finally, the use of naturally cytotoxic effector cells such as natural killer and cytokine-induced killer cells has been proposed in several clinical trials. The clinical development of these latter cells could also be further expanded by additional genetic modifications using the CAR technology. © 2015 Macmillan Publishers Limited.

Topp M.S.,Universitatsklinikum Wurzburg | Gokbuget N.,Goethe University Frankfurt | Stein A.S.,City of Hope | Zugmaier G.,Amgen | And 21 more authors.
The Lancet Oncology | Year: 2015

Background: Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. Methods: In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. Findings: Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. Interpretation: Single-agent blinatumomab showed antileukaemia activity in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia characterised by negative prognostic factors. Further assessment of blinatumomab treatment earlier in the course of the disease and in combination with other treatment approaches is warranted. © 2015 Elsevier Ltd.

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