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Inositide-dependent signalling pathways regulated by phosphoinositide-specific phospholi- pase C (PI-PLC) beta1 have been demonstrated to play important roles in MDS pathogenesis and in cell differentiation (1). Moreover, the MDS therapy aims at inducing myeloid and/or erythroid differentiation of MDS stem cells. Indeed, azacitidine is a demethylating agent that can induce myeloid differentiation. On the other hand, lenalidomide may restore a normal erythropoiesis. The exact molecular mechanisms underlying the effect of azacitidine and lenalidomide in MDS cells are still unclear, although it is clear that these therapies regulate stem cell proliferation, differentiation and apoptosis (2). The combination of azacitidine and lenalidomide in MDS therapy is now under considera- tion, given the capability of both drugs to balance proliferation and differentiation processes (3). In this study we analyzed the molecular effect of this combination therapy on PI-PLC isoenzymes, not only studying PI-PLCbeta1, but also PI-PLCgamma1, that can be associated with erythropoiesis. We analyzed 44 patients diagnosed with high-risk MDS who were given azacitidine and lenalidomide. Given the limited number of cells, we quantified the expression of these molecules by Real-Time PCR analyses and immunocytochemical experiments. Moreover, we carried out cell cycle analyses and studied both PI-PLCbeta1 methylation status and the expression of Globin genes. In our case series, 28/44 patients were evaluable, with an overall response rate of 78.6% (22/28 cases). At a molecular level, a significant increase of PI-PLCbeta1 and/or PI-PLCgamma1 expression was associated with a favourable clinical response to the combination therapy. Responder cases also showed an increase of Beta-globin expression, hinting at a specific contri- bution of lenalidomide on erythroid activation, whilst the frequent demethylation of PI-PLCbeta1 promoter could be specifically linked to azacitidine. Taken together, our results show that the combination of azacitidine and lenalidomide can be important for activating PI-PLC isoenzymes, therefore regulating myeloid and erythroid dif- ferentiation in MDS cells., Italian Journal of Anatomy and Embryology, Vol. 120, No. 1 (Supplement) 2015

Akt is implicated in erythropoiesis, through PI-PLCgamma1, but is also connected with cell cycle and protein synthesis, via activation of the mTOR pathway (1). Lenalidomide is currently used in the treatment of low-risk MDS patients showing a del(5q) karyotype, as it induces erythropoiesis in non-del(5q) cells and selectively inhibits cell proliferation in del(5q) cells (2). However, the exact molecular mechanisms underlying the effect of Lenalidomide in del(5q) and non-del(5q) MDS cells are still unclear, although Lenalidomide demonstrated an effect on targeting signalling molecules involved in apoptosis, proliferation and differentiation, i.e. Akt (3). Here we analyzed the effect of Lenalidomide on two cell lines: Namalwa CSN.70, bearing a del(5q) karyotype, and U937, with a normal 5q chromosome. In particular, we analyzed several molecules implicated in inositide signalling, such as Akt, mTOR and PI-PLCgamma1, as well as Cyclins and Globin genes, in order to assess the effect of Lenalidomide on cell cycle and erythropoiesis. Moreover, we quantified the gene expression profile of 6 patients diagnosed with del(5q) Low-Risk MDS (IPSS: Low or Int-1) who were given Lenalidomide. In our case series, as well as in cell lines, erythropoiesis activation was associated with a response to Lenalidomide, with an induction of Akt/PLCgamma1 and an increase of Beta-Globin. Moreover, only in non-del(5q) cells, a normal proliferation was allowed, given that del(5q) cells showed a cell cycle arrest and a slight inhibition of the Akt/mTOR pathway, this latter being confirmed also by co-localization experiments performed on primary cells from MDS patients. Therefore, our data support the hypothesis of a specific activation of both inositide-dependent proliferation and erythroid differentiation pathways in response to Lenalidomide treatment in non-del(5q) cells, whereas in the del(5q) cell clone there is a cell cycle arrest and a slower erythroid differentiation. Taken together, these results hint to a specific activation of inositide-dependent signalling pathways during Lenalidomide administration and possibly pave the way to a larger investigation aiming to assess the role of these pathways during the therapy., Italian Journal of Anatomy and Embryology, Vol 119, No 1 (Supplement) 2014

Background. Nelarabine (N) is approved for the treatment of T-ALL and T-LBL that have not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Aim. To evaluate safety profile and efficacy of N as savage therapy in 16 adult relapsed or refractory T-ALL or T-LBL. Methods. After obtaining an informed consent, 16 patients (median age 33 years, range 19-45, M/F = 13/3) affected by T-ALL (n=10) and T-LBL (n=6) received savage therapy with N (median cycle=1, range 1-3), administered at standard adult dosage (1500 mg/sqm on days 1, 3 and 5, every 21). Four patients were primary resistant to induction treatment, 7 patients were relapsed after two previous chemotherapy regimens (including allogeneic BMT in 4 cases and autologous SCT in 1 case); the remaining 6 patients had a molecular relapsed disease (MRD positive). Molecular characterization was performed, including NOTCH and WT-1 genes mutational status. GEP analysis, according to Ferrando A. stratification (Cancer Cell 2002), is still ongoing. Results. Currently, 12 out of 16 patients are evaluable, due to a too short follow up in the other 4 cases. Seven out of 12 patients obtained a complete remission (CR) (5 T-ALL 2 T-LBL);a partial remission (PR) was documented in 2 cases, with an overall response rate (ORR) of 75%. Median duration of CR was 10 weeks (range 2.8-54+). Among these, 2 out of 4 patients in molecular relapse reached a molecular CR and underwent an allogenic BMT (currently in CR after a median follow up of 12 months). Extra- hematological toxicity, not clearly related to the drug, occurred in 3 cases, determining, a complete and irreversible paraplegia, a condition of mental confusion, and a peripheral neuropathy, respectively. Conclusions. N showed a strong efficacy also in cases with low levels of residual disease, in addition to a good safety profile. Neurological toxicity needs to be strictly monitored. Acknowledgments. European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione – Università 2007 – 2009.

Background. Approximately 30% of adult ALL patients are characterized by the presence of the Philadelphia (Ph) chromosome, which derives from a reciprocal translocation t(9;22)(q34;q11) and results in a chimeric BCR-ABL oncogene. The prognosis of this subset of patients treated with standard therapies, including multi-agent chemotherapy, Imatinib, and allogeneic stem cell transplantation, is still dismal, due to a high risk of relapse. Dasatinib and Nilotinb are second generation TKIs developed to overcome the problem of resistance to Imatinib in relapsed Ph+ leukemias. Design and Methods. We retrospectively evaluated the single center experience on therapy efficacy of Dasatinib, Nilotinib, and experimental third generation TKIs, administered as second or subsequent line of therapy on 25 relapsed Ph+ adult ALL patients. All patients were previously treated with Imatinib. The median age at time of diagnosis was 50 years (range 18-74), 17 patients were male and 8 female. Ten patients presented a BCR-ABL P190 fusion protein and corresponding fusion transcript, the remaining a BCR-ABL P210. Nineteen patients received Dasatinib, 2 patients Nilotinib and the remaining 4 patients were treated with third generation TKIs. Fourteen patients (56%) were in first relapse, and 7 (28%), 3 (12%) and 1 (4%) were in second, third and fourth relapse, respectively. A mutational analysis was performed in all the patients before TKIs (9 wild type, 16 mutated, including T315I) and at the time of subsequent relapse; gene expression profiling, SNPArray (6.0 Affymetrix chip), and Ikaros deletions were also analyzed. Results. 13 out of 25 patients (52%) obtained a haematological response (HR) (11 patients treated with Dasatinib, 1 patient with Nilotinib and 1 patient with a third generation experimental TKI). 10 patients obtained also a cytogenetic response (CyR) and 6 patients a molecular response (MolR). With a median follow up of 10.8 months (range 2-29 months), median duration of HR, CyR and MolR were 117 days (range 14-385 days); progression free survival were 162 days with Dasatinib and 91 days with Nilotinib. Overall survival was 25.8 months. Interestingly, in 6 out of 9 wild-type patients, treated with Dasatinib, the mutational analysis showed the emergence of T315I or F317I mutation at the time of relapse. Conclusion. Second and third generation TKIs represent a valid approach in relapsed Ph+ adult ALL patients; the subsequent relapse is often associated to the emergence of mutation, conferring resistance to TKIs.

Introduction. Erythropoiesis is associated with the activation of specific inositide-dependent signalling pathways, such as Akt/PLCgamma1. On the other hand, Akt can also be associated with cell cycle and differentiation in MDS, via activation of mTOR pathway. Lenalidomide is currently used in the treatment of del(5q) low-risk MDS patients, to compensate and counteract the MDS ineffective erythropoiesis and selectively inhibit cell cycle in del(5q) cells. The exact molecular mechanisms underlying the effect of Lenalidomide in del(5q) and non-del(5q) MDS cells are still unclear, even though it is clear that Leanlidomide can target signalling molecules playing a role in the maintenance of the balance between apoptosis, proliferation and differentiation, such as Akt. Methods.We studied 6 patients diagnosed with del(5q) Low-Risk MDS (IPSS: Low or Int-1) who were given Lenalidomide. We also analyzed the effect of Lenalidomide on two cell lines: Namalwa CSN.70, bearing a del(5q) karyotype, and U937, with a normal 5q chromosome. In particular, we quantified the expression of several genes implicated in inositide signalling, such as Akt, mTOR and PI-PLCgamma1, as well as Cyclins and Globin genes, in order to assess the effect of Lenalidomide on cell cycle and erythropoiesis. Results. In our case series, 4 out of 6del(5q) Low-Risk MDS patients responded to Lenalidomide and showed an activation of erythropoiesis, in that Beta-Globin levels increased. Moreover, these subjects also displayed a specific phosphorylation of Akt only in non-del(5q) cells, as assessed by co-localization experiments. As for the other 2 cases, patients early discontinued Lenalidomide for adverse events, and for these patients a clinical assessment of Lenalidomide effect was not possible. As for cell lines, our findings hint at a specific activation of cell cycle and erythropoiesis only in U937 cells, whereas cell cycle, but not erythropoiesis, was selectively inhibited in Namalwa CSN.70 cell line, so that in these cells proliferation is slower than in non-del(5q) cells. Conclusions. In our case series, as well as in cell lines, erythropoiesis activation is associated with a response to Lenalidomide, with an induction of Akt/PLCgamma1. Moreover, only in non-del(5q) cells, a normal proliferation is allowed, given that in del(5q) cells our analyses show a cell cycle arrest and an inhibition of Akt/mTOR pathway. Therefore, our data support the hypothesis of a specific activation of both inositide-dependent proliferation and erythroid differentiation pathways in response to Lenalidomide treatment in non-del(5q) cells, whereas in the del(5q) cell clone there is a cell cycle arrest and a slower erythroid differentiation. Taken together, these results point to a specific activation of signalling pathways during Lenalidomide administration and possibly pave the way to a larger investigation aiming to assess the role of these pathways during the therapy.

Sulla base delle evidenze della letteratura (Fenaux, 2009; Lyons, JCO 2009), a partire da Settembre 2004 nel Nostro Istituto sono stati trattati 57 pazienti affetti da Sindrome Mielodisplastica (MDS) mediante terapia demetilante con 5-Azacitidina. Sono stati utilizzati differenti regimi terapeutici a seconda della classe di rischio IPSS: i pazienti a rischio basso/intermedio-1 hanno ricevuto Azacitidina 75 mg/mq/die sottocute per 5 giorni/mese (schema 5) per 8 cicli; i pazienti a rischio alto/intermedio-2 hanno ricevuto Azacitidina 50 mg/mq/die sottocute per 10 giorni/mese (schema 5+2+5) o Azacitidina 75 mg/mq/die per 7 giorni/mese (schema 7) fino a perdita della risposta. Su una casistica totale di 57 pazienti (15 a rischio basso/int-1; 41 rischio alto/int-2), l’87.7% (50 pazienti) sono risultati valutabili. Tra questi le risposte osservate sono state del 68% (34 pazienti), di cui il 14% (7 pazienti) ha ottenuto una Remissione Completa (CR) ed il 54% (27 pazienti) ha ottenuto un Hematologic Improvement (HI). La valutazione della risposta è stata eseguita secondo i criteri dell’International Working Group 2006 (IWG, Cheeson 2006). Le principali tossicità osservate sono state rappresentate da reazioni cutanee locali nel sito d’iniezione, tossicità gastrointestinale (stipsi e/o diarrea), mielotossicità, neutropenia febbrile, sepsi (3 pazienti). Tra i pazienti trattati abbiamo osservato la presenza di risposta ematologica prolungata (≥ 20 mesi) in 10 pazienti (20% dei pazienti valutabili). Inoltre, grazie alla collaborazione con il Dipartimento di Anatomia Umana dell’Università di Bologna (Prof. L. Cocco, Dott.ssa M.Y. Follo), tutti i pazienti trattati sono stati valutati per i livelli di espressione genica e metilazione del gene della fosfolipasi PI-PLC-beta1. I dati biologici così ottenuti sono stati correlati con quelli clinici, evidenziando la presenza di una correlazione tra i livelli di espressione genica e mutilazione della PI-PLC-beta1 e la risposta alla terapia demetilante con 5-Azacitidina., Based on the evidence of literature (Fenaux 2009; Lyons 2009), from September 2004, in our Institute, 57 patients (pts) with Myelodysplastic Syndrome were treated (MDS) with demethylating therapy. We used 4 different regimens depending on the class of IPSS risk: patients at risk low/int-1 received Azacitidine 75 mg/sqm/day subcutaneously for 5 days/month (AZA 5) for 8 cycles, patients at risk high/int-2 received Azacitidine 50 mg/sqm/day subcutaneously for 10 days/month (AZA 5-2-5) or Azacitidine 75 mg/sqm/day for 7 days/month (AZA 7) until loss of response. On a series total of 57 pts (15 lower risk; 41 higher risk), 87 .7% (50 pts) were evaluable. Among these, responses observed were 68% (34 pts): 14% (7 pts) achieved complete remission (CR) and 54% (27 pts) had a Hematologic Improvement (HI). The assessment of response was performed according to the criteria of the International Working Group 2006 (Cheeson 2006). The main toxicities observed were represented by local skin reactions at the injection site, gastrointestinal toxicity (constipation and/or diarrhea), myelotoxicity, febrile neutropenia, sepsis (3 pts). Among the patients we observed the presence of prolonged hematologic response (≥ 20 months) in 10 pts (20% of evaluable patients). In addition, thanks to the collaboration with the Department of Human Anatomy, University of Bologna (Prof. L. Cocco, Dr. Follo MY), all patients were evaluated for levels of gene expression and gene methylation of phospholipase PI PLC- ß 1. The biological data obtained were correlated with clinical, highlighting the presence of a correlation between the levels of gene expression and mutilation of PI-PLC-ß1 and response to therapy with demethylating 5-Azacitidine.

Background. Precursor T cell ALL/LBL occurs most frequently in late childhood, adolescence, and young adulthood, with a 2:1 male predominance; it comprises 15 and 25 percent of childhood and adult ALL, respectively, and 2 percent of adult non-Hodgkin lymphoma. In adult patients prognosis is poor, due to the high incidence of relapse even after allogenic stem cell transplantation. Design and Methods. We retrospectively analysed and currently report clinical outcome results about 52 newly diagnosed and younger than 60 years T-ALL patients (median age 30 years, range 14-73 years; 37/15 M/F; 41/52 T-ALL e 11/52 T-LBL) treated, from 1991 to 2011 according to standard chemotherapy regimen, including adapted pediatric-like schedule (10 pts), BFM protocol (3 pts) and adult schedules (39 pts). After induction, all the patients underwent consolidation for at least one course. All the patients shared the same strategy for intensification, that consisted, when available, in allogenic or autologous stem cell transplantation. Detailed data about cytogenetics and molecular biology will be provided on site. Durations of complete remission (CR) and overall survival (OS) were estimated according to the Kaplan-Meier method. The CR duration was calculated from start of CR to first evidence of disease recurrence. Results. Informed consent was obtained; after a single induction course 41/52 patients obtained a CR (78.8%) and 2 patients a partial remission (PR) (3.8%) for an overall response rate (ORR) of 82.6%. Seven patients (13.4%) had resistant disease, and 2 (3.8%) died during induction. After a median follow-up of 22.7 months, 19 patients (36.5%) are still in CR. The median CR duration and OS were 12.3 and 23.15 months, respectively. The most common grade 3 adverse events included gastro-intestinal toxicities (i.e. nausea, vomiting, mucositis and diarrhoea) and liver dysfunction. Conclusions. Our analysis confirms, in line with literature data, that, despite intensive chemotherapeutic treatments and stem cell transplantation, TALL and T-LBL adult patients still show a bad prognosis. The relatively satisfying induction remission rate is followed, in most cases, by a high relapse rate. Therefore, a molecular stratification approach, based on gene-expression profile analysis (Ferrando et al, Cancer Cell 2002) should be routinely performed, in order to identify new targets, to optimize therapy, to reduce toxicity and to improve clinical outcome. Supported by: European LeukemiaNet, AIRC, AIL, PRIN 2010-2011, Fondazione del Monte di Bologna e Ravenna.

Background. Precursor T cell LBL/ALL occurs most frequently in late childhood, adolescence, and young adulthood, with a 2:1 male predominance; it comprises 15 and 25 percent of childhood and adult ALL, respectively, and 2 percent of adult non-Hodgkin lymphoma. Nelarabine is an anticancer prodrug of arabinofuranosylguanine (ara-G); it inhibits DNA synthesis and leads to high molecular weight DNA fragmentation and cell death. Nelarabine has showed relevant efficacy in phase II clinical trials, both in pediatric and in adult LBL/ALL populations. Design and Methods. We report clinical outcome results of 9 newly diagnosed and younger than 60 years T-ALL patients (median age 29 years, range 22-45 years, 3/6 M/F, 8 T-ALL, 1 T-LBL) treated according to pediatriclike adapted schedule. Cytogentics data and molecular biologic features will be provided on site. Induction cycle included Vincristine, daunoblastine, L-asparaginase and Prednisone. After induction, all the patients received consolidation therapy with cyclophosphamyde, L-asparaginase, Cytarabine and 6-Mercaptopurine. Subsequently all the patients receveid Nelarabine 1500 mg/sqm (days 1-3-5 every 21) for two cycles. All the patients shared the same strategy for intensification, which consisted in allogenic stem cell transplantation, if available, or additional courses of consolidation chemotherapy. Durations of complete remission (CR) and overall survival (OS) were estimated according to the Kaplan-Meier method. The CR duration was dated from start of CR to first evidence of disease recurrence. Results. After a single induction course, 9/9 patients obtained a CR (100%). Eight patients underwent an allogenic bone marrow transplantation. After a median follow-up of 24 months, 7/9 patients (78%) are alive in CR. The median CR duration and OS were 13.4 and 24.4 months, respectively. Neurological toxicity of grade 3 has not been reported. We did not observe grade 3-4 haematological toxicity. Conclusions. Nelarabine is a promising drug, which induces a remarkable complete remission rate at the expense of a very low and manageable toxicity. Acknowledgments. European LeukemiaNet, AIL, AIRC, PRIN 2010-2011, Fondazione del Monte di Bologna e Ravenna.

Sulla base delle evidenze della letteratura (Fenaux, 2009; Lyons, JCO 2009), a partire da Settembre 2004 nel Nostro Istituto sono stati trattati 57 pazienti affetti da Sindrome Mielodisplastica (MDS) mediante terapia demetilante con 5-Azacitidina. Sono stati utilizzati differenti regimi terapeutici a seconda della classe di rischio IPSS: i pazienti a rischio basso/intermedio-1 hanno ricevuto Azacitidina 75 mg/mq/die sottocute per 5 giorni/mese (schema 5) per 8 cicli; i pazienti a rischio alto/intermedio-2 hanno ricevuto Azacitidina 50 mg/mq/die sottocute per 10 giorni/mese (schema 5+2+5) o Azacitidina 75 mg/mq/die per 7 giorni/mese (schema 7) fino a perdita della risposta. Su una casistica totale di 57 pazienti (15 a rischio basso/int-1; 41 rischio alto/int-2), l’87.7% (50 pazienti) sono risultati valutabili. Tra questi le risposte osservate sono state del 68% (34 pazienti), di cui il 14% (7 pazienti) ha ottenuto una Remissione Completa (CR) ed il 54% (27 pazienti) ha ottenuto un Hematologic Improvement (HI). La valutazione della risposta è stata eseguita secondo i criteri dell’International Working Group 2006 (IWG, Cheeson 2006). Le principali tossicità osservate sono state rappresentate da reazioni cutanee locali nel sito d’iniezione, tossicità gastrointestinale (stipsi e/o diarrea), mielotossicità, neutropenia febbrile, sepsi (3 pazienti). Tra i pazienti trattati abbiamo osservato la presenza di risposta ematologica prolungata (≥ 20 mesi) in 10 pazienti (20% dei pazienti valutabili). Inoltre, grazie alla collaborazione con il Dipartimento di Anatomia Umana dell’Università di Bologna (Prof. L. Cocco, Dott.ssa M.Y. Follo), tutti i pazienti trattati sono stati valutati per i livelli di espressione genica e metilazione del gene della fosfolipasi PI-PLC-beta1. I dati biologici così ottenuti sono stati correlati con quelli clinici, evidenziando la presenza di una correlazione tra i livelli di espressione genica e mutilazione della PI-PLC-beta1 e la risposta alla terapia demetilante con 5-Azacitidina., Based on the evidence of literature (Fenaux 2009; Lyons 2009), from September 2004, in our Institute, 57 patients (pts) with Myelodysplastic Syndrome were treated (MDS) with demethylating therapy. We used 4 different regimens depending on the class of IPSS risk: patients at risk low/int-1 received Azacitidine 75 mg/sqm/day subcutaneously for 5 days/month (AZA 5) for 8 cycles, patients at risk high/int-2 received Azacitidine 50 mg/sqm/day subcutaneously for 10 days/month (AZA 5-2-5) or Azacitidine 75 mg/sqm/day for 7 days/month (AZA 7) until loss of response. On a series total of 57 pts (15 lower risk; 41 higher risk), 87 .7% (50 pts) were evaluable. Among these, responses observed were 68% (34 pts): 14% (7 pts) achieved complete remission (CR) and 54% (27 pts) had a Hematologic Improvement (HI). The assessment of response was performed according to the criteria of the International Working Group 2006 (Cheeson 2006). The main toxicities observed were represented by local skin reactions at the injection site, gastrointestinal toxicity (constipation and/or diarrhea), myelotoxicity, febrile neutropenia, sepsis (3 pts). Among the patients we observed the presence of prolonged hematologic response (≥ 20 months) in 10 pts (20% of evaluable patients). In addition, thanks to the collaboration with the Department of Human Anatomy, University of Bologna (Prof. L. Cocco, Dr. Follo MY), all patients were evaluated for levels of gene expression and gene methylation of phospholipase PI PLC- ß 1. The biological data obtained were correlated with clinical, highlighting the presence of a correlation between the levels of gene expression and mutilation of PI-PLC-ß1 and response to therapy with demethylating 5-Azacitidine.

To detect factors associated with quality of life (QOL) of patients with myelodysplastic syndrome (MDS) and to compare the MDS patients’ self-assessed QOL with that perceived by their physicians. In an observational, non-interventional, prospective, multicentre study, QOL was evaluated in 148 patients with newly diagnosed low- and intermediate-risk IPSS MDS. QOL measures (QOL-E v.2, LASA and EQ-5D) and patient-related candidate determinants of QOL were assessed for up to 18 months. Patients' QOL scores were compared with those obtained by appointed hematologists’ assessment and with ECOG performance status (PS). Fatigue was not prevalent at diagnosis, though physical QOL and energy levels were low. Transfusion-dependent patients had worse QOL scores. In multivariate analysis, Hb levels and comorbidities were a major determinant of QOL. Physicians’ perception of patients’ well-being correlated with patients’ QOL. Physicians underestimated the impact of disturbances on patients’ QOL, mainly in the MDS-specific components. ECOG PS did not discriminate patients according to QOL status. In conclusion, the association of anemia with QOL is confirmed, while co-morbidities emerge as an independent predictor of QOL in MDS. Fatigue is not a major concern. ECOG PS is not a valuable surrogate of patient’s QOL, thus highlighting that physician’s judgment of patient’s well-being must not substitute patient-reported outcomes. Appropriate questionnaires should be used to assess MDS patients’ QOL in order to improve communication and therapeutic choice.

Background. Nelarabine (N) is approved for the treatment of T-ALL and T-LBL that have not responded to or has relapsed after treatment with at least 2 chemotherapy regimens. Aim. To evaluate safety profile and efficacy of N as savage therapy in 16 adult relapsed or refractory TALL or T-LBL. Methods. After obtaining an informed consent, 16 patients (median age 33 years, range 19-45, M/F= 13/3) affected by TALL (n=10) and T-LBL (n=6) received savage therapy with N (median cycle=1, range 1-3), administered at standard adult dosage (1500 mg/sqm on days 1, 3 and 5, every 21). Four patients were primary resistant to induction treatment, 7 patients were relapsed after two previous chemotherapy regimens (including allogeneic BMT in 4 cases and autologous SCT in 1 case); the remaining 6 patients had a molecular relapsed disease (MRD positive). Molecular characterization was performed, including NOTCH and WT-1 genes mutational status. GEP analysis, according to Ferrando A. stratification (Cancer Cell 2002), is still ongoing. Results. Currently, 12 out of 16 patients are evaluable, due to a too short follow up in the other 4 cases. Seven out of 12 patients obtained a complete remission (CR) (5 T-ALL 2 T-LBL);a partial remission (PR) was documented in 2 cases, with an overall response rate (ORR) of 75%. Median duration of CR was 10 weeks (range 2.8-54+). Among these, 2 out of 4 patients in molecular relapse reached a molecular CR and underwent an allogenic BMT (currently in CR after a median follow up of 12 months). Extra- hematological toxicity, not clearly related to the drug, occurred in 3 cases, determining, a complete and irreversible paraplegia, a condition of mental confusion, and a peripheral neuropathy, respectively. Conclusions. N showed a strong efficacy also in cases with low levels of residual disease, in addition to a good safety profile. Neurological toxicity needs to be strictly monitored. Acknowledgments. European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione – Università 2007 – 2009.

Italian Journal of Anatomy and Embryology, Vol 115, No 1/2 (Supplement) 2010