In this contribution, new data concerning the distribution of vascular flora alien to Italy are presented. It includes new records, confirmations, exclusions for Italy or for Italian administrative ...regions. Nomenclatural and distribution updates, published elsewhere, and corrections are provided as Suppl. material 1.
Histone deacetylases (DACs) are involved in chromatin structure regulation and function. Treatment with DACs inhibitors leads to the activation or repression of genes regulating apoptosis, ...proliferation, differentiation, angiogenesis, immune responses. These agents resulted to be active for the treatment of T and B-cell lymphoma and other haematological malignancies. Previous in vitro studies underlined the possible pathophysiological role of DACs in diffuse large B-cell lymphoma (DLBCL). In FIL-PanAL10 we evaluate the therapeutic activity and safety of Panobinostat, a potent pan-DACs inhibitor, in patients with relapsed or refractory (R/R) DLBCL.
FIL-PanAL10 (NCT01523834) is a phase II, prospective multicenter trial of the Fondazione Italiana Linfomi (FIL). Enrolled patients are ≥ 18 years old with R/R DLBCL, following ≥ 1 line of chemo-immunotherapy (R-CHOP) including high dose therapy with autologous stem cell support (ASCT) in eligible patients. Patients with > 5 prior systemic lines of treatment, CNS involvement, HIV positivity, impaired cardiac function (according to the protocol) are excluded. Patients are scheduled to receive Panobinostat po 40 mg three-times every week as part of a 4-weeks treatment cycle up to disease progression, unacceptable toxicity, or patient's refusal. The primary endpoint of the study is to explore the antitumor activity of Panobinostat in terms of overall response (ORR) according to the Cheson criteria 1999. Secondary objectives are the evaluation of complete response (CR), time to response (TTR), progression free survival (PFS), overall survival (OS) and safety. Exploratory objectives evaluate the predictive role of pharmacogenetics, immunohistochemical and specific gene expression in relation to the response to Panobinostat; for this aim a new lymph node or other pathologic tissue biopsy is requested before starting treatment. With the null (P0) and P1 hypothesis of overall response (ORR) corresponding to <10% and ≥ 30%, 35 patients will be needed (α: 0.5; β: 0.10) and at the end of the trial treatment with Panobinostat will be considered active if ≥ 7 responses will be occurred.
Between February 2011 and May 2013, 23 patients were enrolled on this study. Patients' median age is 73 years (range 44-83 years); 7 (30%) patients received ≥ 3 previous lines of chemotherapy. Five patients responded to Panobinostat (ORR= 22%) including 3 CR (13%) and 2 (9%) partial response (PR): 1 patient had (4%) stable disease (SD). TTR was 2.5 months (range 2-3 months ). All 6 patients with ORR or SD are still in treatment with Panobinostat after 4, 5, 12, 12, 15, 24, months; 17 patients discontinued therapy because of progression (15) or side effects (2). After a median period of observation of 11 months from the beginning of treatment, 1-year PFS and OS are 22% and 28%, respectively. Most common observed grade 3-4 adverse events were hematological and included thrombocytopenia (88%) and neutropenia (34%); grade 3-4 diarrhoea was present in 3 (13%). The therapeutic schedule was modified from the three times week to three times every other week in 15 patients; a further dose reduction from 40 mg to 30 mg resulted to be necessary in 8 patients. The analysis of exploratory biologic objectives and of their relationship with outcome is still under investigation and will be ready for December 2013.
The preliminary results of this study indicates that Panobinostat is an active salvage therapy in nearly 20% of heavily pretreated R/R DLBCL patients; the relatively short TTR observed allows a prompt shift to other rescue treatments in non responders. The analysis of biologic biomarkers will hopefully better address Panobinostat therapy to a specific biologic subgroup.
Zaja:Mundipharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy; GSK: Consultancy, Honoraria; Amgen: Consultancy. Off Label Use: Panobinostat in DLBCL.
Background: Colorectal cancer (CRC) metastasis is enhanced in patients with venous embolization increasing the risk of recurrence and therefore mortality rate. Several evidences indicate that stage ...II patients have an abrupt recurrence within five years from surgery. This fact, led us to investigate the role played by different histological variables on CRC invasiveness. Aim: To demonstrate if quantitative and qualitative desmoplastic response and lymphocytic infiltration are prognostic factor involved in the recurrence of CRC within five years from surgery, considering possible clinical and therapeutical implications. Methods: Thirty-four patients with CRC underwent colectomy and the UICC-TNM classification was applied for disease staging. Histological variables were semi-quantitatively evaluted. Qualitative evaluation of desmoplasia was obtained with the hematoxillin-eosin method. Results: Survival rate arose 88% at stage II, at five years of follow-up, and the 12% not treated with adiuvant chemotherapy developed metastasis. Desmoplasia is strongly associated with venous neoplastic invasiveness (OR: 21.93; 95%CI: 1.012-475.26, p = 0.02), and therefore, with mortality rate (OR: 14.33; 95%CI: 0.67-304, p = 0.04). Moreover, mortality rate was significantly higher in patients with immature desmoplasia compare to mature stromal tissue (OR: 15.61, 95%CI: 0.69-343.38, p = 0.04). Conclusions: These observations should prompt a future evaluation of desmoplasia to extent more suitably the use of adjuvant chemotherapy in II stage patients. Further clinical trials are needed to determine if these findings will be able to reduce mortality rate, in stage II CRC patients.
Abstract 2149
Poster Board II-126
Autologous stem cell transplantation (ASCT) is a potentially curative treatment for lymphoma. Adequate stem cell (SC) collection is possible in the majority of cases ...but poor mobilization remains a major issue in some patients (pts). New agents were recently developed which may improve the rate of SC mobilization.
A retrospective analysis was conducted on a large series of lymphoma pts candidates to ASCT in order to identify factors influencing SC mobilization outcome. Potential early markers of poor mobilization were also evaluated.
A total of 415 attempts of PBSC collection consecutively performed at 7 Italian centres in 388 pts affected by lymphoma were analyzed. Their median age was 52. A collection of less than 2×106 CD34+ cells/kg was defined as “mobilization failure” and of more than 5×106 CD34+ cells/kg as “good mobilization”. The following parameters were analysed for correlation with mobilization outcome: lymphoma diagnosis, disease status at mobilization, type of mobilizing chemotherapy, bone marrow infiltration at collection, n° of previous lines of therapy, prior use of fludarabine, alkylating agents or radiotherapy. The ratio between circulating CD34+cells/nL and total WBC/μL on the first day of CD34+ count (SCratio) was also analysed, trying to predict mobilization failure. Both univariate and multivariate statistical analyses were performed with SPSS package 13.0.
Lymphoma diagnosis was diffuse large B cell/Burkitt in 38%, follicular in 10%, mantle in 13%, Hodgkin in 26%, T or NK/T in 6%, and other in 7% of cases. Disease status at apheresis was CR in 25%, chemosensitive in 49% and refractory in 26%. Mobilization was attempted during first-line therapy in 14%, in 37% during second-line and in 26% at third- or subsequent lines of therapy. Fludarabine, alkylating agents and extended-fields radiotherapy had been used prior to mobilization in 5%, 73% and 13% of cases respectively. Marrow infiltration by lymphoma was present in 17,7% and 7,7% of patients had failed a prior mobilization attempt.
In 99% of cases (411/415) mobilizing therapy included chemotherapy and G-CSF. Two pts received AMD3100 and 2 G-CSF. Several chemotherapy programs were used for mobilization. For analysis purposes they were grouped as follows: single-agent cyclophosphamide (CTX) in 62 (15,1%); high-dose cytarabine, either single agent or in combination (HD-ARAC) in 143 (34,8%), etoposide-containing regimens in 119 (30,0%), and platinum containing regimens in 108 cases (26,3%).
Mobilization failure occurred in 14% (59/415) whereas a good mobilization was obtained in 72% of cases. At univariate analysis mobilization failure was significantly associated with the use of single-agent CTX as mobilizer (p=0.000), with the n° of prior lines of treatment (p=0.006) and with failure of a previous mobilization attempt (p=0.000) whereas a diagnosis of follicular lymphoma (FL) was associated with a reduced risk of mobilization failure (p=0.007). Multivariate analysis confirmed FL as protective factor for mobilization failure (p=0.008) and single agent CTX and a higher n° of prior treatment lines as negative predictive factors (p=0.000 and 0.033 respectively).
A “good mobilization” was significantly predicted at univariate analysis by HD-ARAC use as mobilizer (p=0,004) whereas single-agent CTX (p=0.000), n° of prior lines of therapy (p=0.005), prior fludarabine (p=0.035) or alkylating agents (p=0.003) were adverse predictors. Multivariate analysis confirmed HD-ARAC as independent predictive factor for good mobilization (p=0.031) and single-agent CTX and n° of prior lines of therapy as independent negative predictive factors (p=0.000 and 0.003 respectively). A SCratio of less than 10 on the first day of CD34+ count was associated with an increased risk of poor mobilization (p=0.000 risk estimate 0.638).
In this large series of pts with lymphoma the standard policy of SC mobilization was the use of chemotherapy + G-CSF. Nevertheless collection failed in a significant proportion of cases (14 %) and only 72% of cases reached an optimal SC collection. Predictive factors for mobilization outcome included disease and treatment history, type of lymphoma and type of mobilizing chemotherapy. These data provide the framework to rationally explore the use of new mobilizing agents in patients with lymphoma undergoing SC mobilization with chemotherapy and G-CSF.
No relevant conflicts of interest to declare.
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