Purging e alte dosi di chemioterapia con reinfusione di cellule staminali autologhe in linfomi non Hodgkin follicolari resistenti/refrattari

In the era of monoclonal antibodies the role of autologous stem cell transplantation (ASCT) in the management of follicular lymphoma (FL) is still debated. To evaluate the safety and efficacy of myeloablative therapy with rescue of purged or unpurged harvests in FL pts. At our institution form 1997 to 2007 28 pts with refractory/resistant FL were eligible for ASCT. Before high dose therapy they received 2-3 cycles of CHOP-like regimen (ACOD), followed by Cyclophosphamide 4g/mq to mobilize the stem cells (SC). After SC collection the pts underwent 3 cycles of subcutaneous Cladribine at a daily dose of 0,14-0,10 mg/Kg for Day 1-5 every 3-4 weeks. The conditioning regimen was based on Mitoxantrone 60mg/mq + Melphalan 180 mg/mq, followed by SC re-infusion 24-hours later and G-CSF starting 24 hours after re-infusion. In 19 pts the SC underwent purging: in 10 harvests the CD34+ were selected by immunomagnetic beads, while in the other 9 pts, only Rituximab was used as “purging in vivo” agent. The remaining 9 pts received unpurged SC. Before ASCT 11 pts were in complete response (CR), 9 in partial response (PR) and 2 in stable disease. Two pts were not eligible for ASCT because of progressive disease (PD). The remaining 25 pts were eligible for ASCT. The engraftment was at a median of 11 days for leucocytes and 14 days for platelets (>20.000/mmc), with a delay of one day in the pts, who received purged SC. Grade 3-4 mucositis was described in 8 pts. During aplasia a 48% infection rate was reported, without differences between pts with purged or unpurged SC. One patient in CR presented myelodysplastic syndrome at 18 months from ASCT. After ASCT 22 pts were in CR, 2 in PR and one patient were not valuable, because died before response assessment. Nine pts in CR showed PD at a median time of 14 months from ASCT. With a median follow up of 5 years (range 2 months -10 years), 22 pts are alive and 11 (44%) in CR. Ten pts died, 5 for progressive disease and 5 for treatment-related causes; in particular 7 of them received in-vitro purged SC. Conclusions: Our chemotherapy regimen, which included the purine analogue Cladribine in the induction phase, seems safe and feasible. The high rate of CR reported and the sustained freedom from progression up to now, makes such modality of treatment a valid option principally in relapsing FL patients. In our experience, the addition of a monoclonal antibody as part of treatment confirms its role “in vivo purging” without observing an increased incidence of infection.

Development and performance assessment of a Plasma Focus electron beam generator for Intra-Operative Radiation Therapy

The Plasma Focus is a device designed to generate a plasma sheet between two coaxial electrodes by means of a high voltage difference. The plasma is then driven to collapse into a “pinch”, where thermonuclear conditions prevail. During the “pinch phase” charged particles are emitted, with two main components: an ion beam peaked forward and an electron beam directed backward. The electron beam emitted backward by Plasma Focus devices is being investigated as a radiation source for medical applications, using it to produce x-rays by interaction with appropriate targets (through bremsstrahlung and characteristic emission). A dedicated Plasma Focus device, named PFMA-3 (Plasma Focus for Medical Applications number 3), has been designed, put in operation and tested by the research groups of the Universities of Bologna and Ferrara. The very high dose rate (several gray per discharge, in less than 1 µs) is a peculiarity of this device that has to be investigated, as it might modify the relative biological effectiveness (RBE). Aim of this Ph.D. project was to investigate the main physical properties of the low-energy x-ray beams produced by a Plasma Focus device and their potential medical applications to IORT treatments. It was necessary to develop the optimal geometrical configuration; to evaluate the x-rays produced and their dose deposited; to estimate the energy electron spectrum produced in the “pinch phase”; to study an optimal target for the conversion of the x-rays; to conduct simulations to study the physics involved; and in order to evaluate the radio-biological features of the beam, cell holders had to be developed for both irradiations and cell growth conditions.

Trattamento radioterapico ipofrazionato ad alte dosi del carcinoma prostatico con tecnica ad intensità modulata (IMRT) guidata dalle immagini (IGRT)

Obiettivo: valutare la tossicità ed il controllo di malattia di un trattamento radioterapico ipofrazionato ad alte dosi con tecnica ad intensità modulata (IMRT) guidata dalle immagini (IGRT) in pazienti affetti da carcinoma prostatico a rischio intermedio, alto ed altissimo di recidiva. Materiali e metodi: tutti i pazienti candidati al trattamento sono stati stadiati e sottoposti al posizionamento di tre “markers” fiduciali intraprostatici necessari per l’IGRT. Mediante tecnica SIB – IMRT sono stati erogati alla prostata 67,50 Gy in 25 frazioni (EQD2 = 81 Gy), alle vescichette 56,25 Gy in 25 frazioni (EQD2 = 60,35 Gy) e ai linfonodi pelvici, qualora irradiati, 50 Gy in 25 frazioni. La tossicità gastrointestinale (GI) e genitourinaria (GU) è stata valutata mediante i CTCAE v. 4.03. Per individuare una possibile correlazione tra i potenziali fattori di rischio e la tossicità registrata è stato utilizzato il test esatto di Fisher e la sopravvivenza libera da malattia è stata calcolata mediante il metodo di Kaplan-Meier. Risultati: sono stati arruolati 71 pazienti. Il follow up medio è di 19 mesi (3-35 mesi). Nessun paziente ha dovuto interrompere il trattamento per la tossicità acuta. Il 14% dei pazienti (10 casi) ha presentato una tossicità acuta GI G ≥ 2 e il 15% (11 pazienti) ha riportato una tossicità acuta GU G2. Per quanto riguarda la tossicità tardiva GI e GU G ≥ 2, essa è stata documentata, rispettivamente, nel 14% dei casi (9 pazienti) e nell’11% (7 pazienti). Non è stata riscontrata nessuna tossicità, acuta o cronica, G4. Nessun fattore di rischio correlava con la tossicità. La sopravvivenza libera da malattia a 2 anni è del 94%. Conclusioni: il trattamento radioterapico ipofrazionato ad alte dosi con IMRT-IGRT appare essere sicuro ed efficace. Sono comunque necessari ulteriori studi per confermare questi dati ed i presupposti radiobiologici dell’ipofrazionamento del carcinoma prostatico.

Histone deacetylase inhibitors in adult patients with diffuse large b-cell lymphoma relapsed/refractory: a phase II study with Panobinostat

Backgrounds:Treatment of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) not eligible to high dose therapy represents an unmet medical need. Panobinostat showed encouraging therapeutic activity in studies conducted in lymphoma cell lines and in vivo in patients with advanced hematologic malignancies.Purpose:FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL) to evaluate safety and efficacy of single agent Panobinostat as salvage therapy for R/R DLBCL patients and to evaluate a possible relationships between response and any biological features. Patients and Methods:Patients with R/R DLBCL were included. The treatment plan included 6 induction courses with Panobinostat monotherapy followed by other 6 courses of consolidation. The primary objective was to evaluate Panobinostat activity in terms of overall response (OR); secondary objectives were: CR rate, time to response (TTR), progression-free survival (PFS), safety and feasibility of Panobinostat. We included evaluation of the impact of pharmacogenetics, immunohistochemical patterns and patient’s specific gene expression and mutations as potential predictors of response to Panobinostat as explorative objectives. To this aim a pre-enrollment new tissue biopsy was mandatory. ResultsThirty-five patients, 21 males (60%), were enrolled between June 2011 and March 2014. At the end of induction phase, 7 responses (20%) were observed, including 4 CR (11%), while 28 patients (80%) discontinued treatment due to progressive disease (PD) in 21 (60%) or adverse events in 7 (20%). Median TTR in 9 responders was 2.6 months (range 1.8-12). With a median follow up of 6 months (range 1-34), the estimated 12 months PFS and OS were 27% and 30.5%, respectively. Grade 3-4 thrombocytopenia and neutropenia were the most common toxicities (in 29 (83%) and 12 (34%) patients, respectively. Conclusions The results of this study indicate that Panobinostat might be remarkably active in some patients with R/R DLBCL, showing durable CR