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This article enriches current debates about multisided digital platforms focusing on the domain of resilience in the light of microfoundations perspective. Three processes of resilience - anchoring, objectification, and legitimization - are proposed to explain structural and behavioral dimensions of resilience for multisided digital platforms. Three levels are identified: 1) dyadic, 2) organizational, and 3) social/policy through which platforms’ features are explained and the dynamics of resilience within the platform as the result of three microfoundations are decoded. Conceptualization herein can be useful both for strategizing around the platform and for defining policy actions for managing the (un)intended consequences of platform dynamics.

P-glycoprotein (P-170) is the phenotypic marker of tumoral cells that show the phenomenon of multidrug resistance (MDR). Using an immunocytochemical approach, we employed the monoclonal antibody C219 (which recognizes an epitope of such a glycoprotein) to evaluate in cytologic samples the expression of P-170 on neoplastic cells from 52 patients affected by different hematologic malignancies and its eventual correlation to clinical outcome. Longitudinal studies were also performed in 14 patients. Results obtained demonstrated that a) the so-called « MDR phenotype » may be heterogeneously represented (from « 1 to 100% of positive cells) in hemopoietic tumors at diagnosis (without exposure to pharmacologic agents), as well as during the course of the disease, although a more substantial presence of P-170 occurred in treated patients. There was no correlation between neoplastic kinetic activity (such as expression of Ki 67 recognized nuclear proliferation-associated antigen) and P-170-positive cells. b) Percentage of positive cells as well as intensity of staining seemed to be important in determining MDR; in general, there was a strong correlation between expression of P-170 in more than 20% of neoplastic cells and a lack of response to chemotherapy. However, some false-positive and false-negative cases were observed. c) The detection of scattered P-170-positive cells may predict a pharmacologic selection of intrinsic or mutant-resistant clones.

Abstract 5032

Combining bortezomib with pegylated liposomal doxorubicin for the treatment of Multiple Myeloma (MM) may reciprocally increase their efficacy in vitro and appears to offer higher overall response rates in vivo. With the aim to verify the synergistic interaction towards myeloma cells we planned a prospective study with bortezomib, non-pegylated liposomal doxorubicin and dexamethason in patients with relapsed/refractory multiple myeloma (R/R MM). In this setting of patients, showing a poor outcome because of multi-drug resistance, low-performance status and toxicity to previous chemotherapy, bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to doxorubicin and overcome drug-resistance. Thus, to improve outcome minimizing therapy-related toxicity, bortezomib was added to non-pegylated liposomal doxorubicin and dexamethason (PAD regimen).From November 2005 and January 2012, 50 patients with R/R MM (relapsed n= 37 and refractory n= 13) referred to the our Institution received PAD regimen. Male/Female ratio: 27/23; Median age: 61 years (range 34–79); median time from diagnosis: 32 months (range 4–121); median of previous therapy lines: n= 3 (range 1–5); patients previously underwent to autologous and allogeneic hemopoietic stem cell transplantation (auto- and allo-HSCT): 22 and 5, respectively. Planned treatment: bortezomib 1, 3 mg/mq iv days 1, 4, 8, 11; non-pegylated liposomal doxorubicin 30 mg/mq on day 1 and dexamethason 40 mg days 1–4 of a 28-day cycle up to 6 cycles.Forty patients (80%) received the planned treatment schedule whereas 10 patients did not complete it because of toxicity (1 patients) and resistant or progressive disease (9 patients). Median time to best response was 3 months (range 2–6). The overall response rate was 74% with 10 CR (20%), 15 vGPR (30%) and 12 PR (24%). Fifteen of the responder patients underwent HSCT (auto-HSCT: 9; allo-HSCT: 6). The previous use of anthracyclines (35 patients) and bortezomib (3 patients) did not seem influence the response. Median duration of response was 24 months (range 6–57 months). After a median follow-up of 58 months, 14 (28%) patients were alive and, of these, 7 (14%) in Continue CR. The safety profile was manageable: the hematologic grade 3/4 toxicity (neutropenia, thrombocytopenia and anemia) was 28%; non-hematologic grade 3/4 toxicity (sensory or motor neuropathy, infections, fever, fatigue, diarrhea) was 36%. Despite heavy previous treatments, including anthracycline-based, no significant cardiac toxicity was observed.According to our study, the PAD regimen appears feasible and effective in both elderly and heavily pre-treated R/R MM patients. In fact a significant improved clinical outcome in our cohort of patients was observed.No relevant conflicts of interest to declare.

Background: Despite the popularity of splenectomy has decreased dramatically in the past few years, the surgical approach remains the best therapy for patients with refractory Immune Thrombocytopenic Purpura (ITP) in terms of high and durable rate of response (Vesely et al, Ann Intern Med2004; 140: 112). The recent introduction of anti-CD20 antibodies and thrombopoietins of second generation such as AMG 531 and Eltrombopag may have a relevant role (Kuter et al, Lancet2008; 371: 362) but their long-term safety and efficacy have not been still established. In parallel with new drugs, there has been an evolution in the surgery of splenectomy as well (Dolan et al, Am J Hematol2008; 83: 93). Actually, the laparoscopic surgery is considered the standard approach and the ITP represents the most common indication in 50–80% of all the laparoscopic splenectomies. Methods: The aim of this study is to evaluate the long-term complete and partial haematological response (CR + PR), as well as the short and long-term complications, of 40 patients (30 females and 10 males; median age: 38 years - range 6–71) with unresponsive ITP after one or more medical approaches and underwent laparoscopic splenectomy at our Institution from 1999 through 2006. The 40 patients accounted for 22.2% of 181 patients diagnosed in those years. An abdominal CT scan to evaluate the presence of accessory spleens was performed in all cases. All patients received meningococcal, pneumococcal and haemophilus influenzae vaccine one week before splenectomy. For 4 or 5 days before splenectomy the patients were treated with high doses of intravenous Immunoglobulins. Anti-thrombotic prophylaxis was performed with low molecular weight heparin (LMWH) for 10 days and afterwards with cardioaspirin (ASA) if the platelet count exceeded 500x10E9/L. Results: No cases required conversion to laparotomic splenectomy. An accessory spleen was found in 2 patients (5%). Immediate haematological response rate was of 100%. At date, after a median follow-up of 78 months (range 28–112 months), 36 patients (90%) remain in CR or PR with a platelet count more than 50x10E9/L and 2 patients are taking ASA. Four patients (10%) relapsed; out of which, 2 patients have a platelet count less than 10x10E9/L. Short and long-term mortality rate was 0%. Immediate postoperative complications rate was 5%: we observed 2 cases of hemoperitoneum related to a trocar’s tube and to an active bleeding, respectively, both resolved with new laparoscopic approach. The mean postoperative hospital stay was 4,5 days (range 4–8). Neither cases of bacterial sepsis in the postoperative or during the follow-up time, nor cases of splenic-portal vein thrombosis (SPVT) and no cases of neoplasms occurred. Conclusions: Our experience suggests that laparoscopic splenectomy is an excellent approach to patients with refractory ITP in terms of safety, efficacy and costs. With respect to laparotomic splenectomy, the use of laparoscopy is likely to make the splenectomy even safer and therefore suitable for a larger number of patients. Undoubtedly there is a great expectation for the new drugs (Rodeghiero et al, Am J Hematol2008; 83: 91) and we agree that only controlled comparative clinical trials (Vianelli et al, Haematologica2005; 90: 72) will be able or not to say a final word and to challenge the role of splenectomy.

Background:Despite the popularity of splenectomy has decreased dramatically in the past few years, the surgical approach remains the best therapy for patients with refractory Immune Thrombocytopenic Purpura (ITP) in terms of high and durable rate of response (Vesely et al, Ann Intern Med 2004; 140: 112). The recent introduction of anti-CD20 antibodies and thrombopoietins of second generation such as AMG 531 and Eltrombopag may have a relevant role (Kuter et al, Lancet 2008; 371: 362) but their long-term safety and efficacy have not been still established. In parallel with new drugs, there has been an evolution in the surgery of splenectomy as well (Dolan et al, Am J Hematol 2008; 83: 93). Actually, the laparoscopic surgery is considered the standard approach and the ITP represents the most common indication in 50–80% of all the laparoscopic splenectomies.

The Combination of Rituximab and CHOP (R-CHOP) is the golden standard in young and elderly NHL therapy, safe and effective. We included pegylated lyposomial Adriamycin (Caelyx®) instead of conventional Adriamycin in R-CHOP regimen in order to reduce myocardic and organ toxicity and to enhance doxorubicin uptake in tumour mass in advanced stage DLBC-NHL of elderly patients with comorbidity. This study is a retrospective study including patients of two haematology centers. We analyzed 34 DLBCNHL patient treated with R-CCOP (Rituximab 375mg/sqm day 0, Caelyx® 30 mg/sqm day 1, cyclophosphamide 750 mg/sqm day 1, Vincristine 1 mg/sqm day 1, Prednisone 100 mg/day, days 1–5, recycle every 21 days). The median number of administered cycles was 6 (Range 4–11). G-CSF was administered according to international guidelines Their median age was 74.5 years old (Range 65–87), M/F:20/14, 19/34 (55%) patients presented stage III– IV disease. 8 (23%) had B symptoms and 11 (32%) extranodal disease.12/34 (35%) patients had IPI high-intermediate and 11/34 (32%) high. 17/34 (50%) showed comorbidity (hepatitis C, NIDDM, severe hypertension, aortic valve disease, atrial fibrillation, chronic renal failure). Median follow-up was 26 months (Range 9–36). Overall (OS) and progression-free survival (PFS) at 36 months were calculated using Kaplan-Mayer method. After R-CCOP therapy we obtained the complete remission in 24/34 (70%) of patients, a very good partial remission in 2/34 (5%). The disease progressed in 3/34 (8%). Five out of 34 (14%) dead (3 of these for disease progression). No severe treatment-related toxicities were observed, except G3-G4 WHO neutropenia in 17 patients (50%) and cardiotoxicity in 2 patients (6%) with pre-existing cardiopathy (bradycardia and atrial fibrillation with high heart rate respectively). Myocardial function was evaluated by 2D echocardiogram before and after chemotherapy treatment and was not impaired by pegylated lyposomial Adriamycin administration. 3% of patients presented severe mucositis and 9% non-fatal infections. We did not observe any thrombocytopenia, In our study OS and EFS at 36 months were respectively 83.7% (95%CI 70.4–97%) and 56% (95%CI 27–85%).Non-responding patients had extranodal, stage IV disease with B symptoms. Nevertheless, they maintained chemosensitivity to a second-line therapy. In elderly B-NHL patients with advanced stage of disease and comorbidity, R-CCOP seems to be safe, feasible and effective. These results confirm and improve in a larger cohort of patients those reported by Zaja, Tulpule and Coiffier in their previous series (see table). Zaja et al Tulpule et al Giordano et al Coiffier et al Treatment R-COP-Caelyx x6 R-COP-Caelyx x8 R-COP-Caelyx x4-11 R-CHOP x8 * in 2 pts with preexisting cardiopathy Patients 29 19 34 202 Caelyx mg/sqm 30 40 30 \ Doxorubicin mg/sqm \ \ \ 50 Age (median) 69 51 74.5 69 IPI (L/IL) 38% 47% 32% 46% IPI IH/H 62% 53% 68% 54% OR 76% 100% 76% 82% CR 59% 80% 71% 76% 2y EFS 65.5% NA (56% 3y) 60% TRM 0 0 0 12/202 (6%) Grade III/IV toxicity Neutropenia 86% 68% 50% 91% Thrombocytopenia 3% 5% 0% NA Mucositis 3% 0% 3% 3% Infection 3% 0% 9% 12% Cardiotocicity 0% 0% 6%* 8%

Background: Autologous Transplantation with intermediate or high doses of Melphalan is the most effective therapy in patients with Multiple Myeloma being < 65 years old, although this procedure is limited by an high percentage of relapses. Recent advances knowledge of the molecular mechanisms, allowed the development of novel targeted therapies. Several studies have shown that the synergic effect of Bortezomib and Talidomidomide, in association with conventional chemotherapies, induces a more pronounced reduction of tumour mass, an enhancement of global responses and an improvement of Progression Free Survival (PFS). Aims: The present study is aimed at the evaluation of effectiveness and toxicity of MVTD conditioning therapy with stem cell support in Multiple Myeloma relapsed patients. Patients and Methods: From January 2005 to August 2007, 15 patients (7 males and 8 females: median age 62 yrs (46–70)) have been subjected to Autologous Transplantation therapy with MVTD conditioning therapy (Melphalan 100 mg/sqm days - 6 and - 3, Bortezomib 1.3 mg/sqm days - 6 and - 3, Talidomide 200 mg from day - 6 to day - 2, Desametazone from day - 6 to day - 3, CSP infusion at day 0). All patients were in CS III A; median performed therapies 3 (1–5); all had received previously a therapy with Talidomide, two Talidomide + Velcade, one PEG-IFN. Results: 100% of patients obtained a response: 4 patients (26.7%) obtained CR, 5 (33.3%) a nCR, 4 (26.7%) a VGPR and 2 (13.3%) a PR. One patient in CR was subjected to 2 therapeutic lines and 3 patients in CR were subjected to more than 1 therapeutic lines, 5 in nCR from 2 to 4, 4 in VGPR from 2 to 4 and 2 in PR more than 2. At the moment, with a median of 7.5 months (1–21), 11 (73%) are alive, 8 (53%) still keep the obtained response, 3 (20%) after progression are in rescue therapy, 4 patients (27%) died because of progression. PFS median since MVTD beginning is of 6 months (1–24). None of the patients have developed a significant neurotoxicity. All patients have developed grade 4 thrombocytopenia and neutropoenia, with a median of 3 days (1–10) and 6 days (4–12), respectively. 54% of patients had neutropoenia with fever with a median of 2 days (0–8). The median units of platelets and red cells infused was 3 (2–11) and 2 (0–11), respectively. Conclusions: In our experience, Autologous Transplantation therapy with MVTD conditioning, appeared to be effective in relapsed patients with Multiple Myeloma. Although in a small series of patients the response obtained was independent from the number and type of previous therapies, from the clinical state, and β2 microglobulin. No significant neurotoxicity has been observed, whether the haematological toxicity was overlapping to that due to conventional Autologous Transplant. Further studies, in larger series of non pluritreated patients are required.

Background: Autologous Transplantation with intermediate or high doses of Melphalan is the most effective therapy in patients with Multiple Myeloma being < 65 years old, although this procedure is limited by an high percentage of relapses. Recent advances knowledge of the molecular mechanisms, allowed the development of novel targeted therapies. Several studies have shown that the synergic effect of Bortezomib and Talidomidomide, in association with conventional chemotherapies, induces a more pronounced reduction of tumour mass, an enhancement of global responses and an improvement of Progression Free Survival (PFS).

The Combination of Rituximab and CHOP (R-CHOP) is the golden standard in young and elderly NHL therapy, safe and effective. We included pegylated lyposomial Adriamycin (Caelyx®) instead of conventional Adriamycin in R-CHOP regimen in order to reduce myocardic and organ toxicity and to enhance doxorubicin uptake in tumour mass in advanced stage DLBC-NHL of elderly patients with comorbidity. This study is a retrospective study including patients of two haematology centers. We analyzed 34 DLBCNHL patient treated with R-CCOP (Rituximab 375mg/sqm day 0, Caelyx® 30 mg/sqm day 1, cyclophosphamide 750 mg/sqm day 1, Vincristine 1 mg/sqm day 1, Prednisone 100 mg/day, days 1–5, recycle every 21 days). The median number of administered cycles was 6 (Range 4–11). G-CSF was administered according to international guidelines Their median age was 74.5 years old (Range 65–87), M/F:20/14, 19/34 (55%) patients presented stage III– IV disease. 8 (23%) had B symptoms and 11 (32%) extranodal disease.12/34 (35%) patients had IPI high-intermediate and 11/34 (32%) high. 17/34 (50%) showed comorbidity (hepatitis C, NIDDM, severe hypertension, aortic valve disease, atrial fibrillation, chronic renal failure). Median follow-up was 26 months (Range 9–36). Overall (OS) and progression-free survival (PFS) at 36 months were calculated using Kaplan-Mayer method. After R-CCOP therapy we obtained the complete remission in 24/34 (70%) of patients, a very good partial remission in 2/34 (5%). The disease progressed in 3/34 (8%). Five out of 34 (14%) dead (3 of these for disease progression). No severe treatment-related toxicities were observed, except G3-G4 WHO neutropenia in 17 patients (50%) and cardiotoxicity in 2 patients (6%) with pre-existing cardiopathy (bradycardia and atrial fibrillation with high heart rate respectively). Myocardial function was evaluated by 2D echocardiogram before and after chemotherapy treatment and was not impaired by pegylated lyposomial Adriamycin administration. 3% of patients presented severe mucositis and 9% non-fatal infections. We did not observe any thrombocytopenia, In our study OS and EFS at 36 months were respectively 83.7% (95%CI 70.4–97%) and 56% (95%CI 27–85%).Non-responding patients had extranodal, stage IV disease with B symptoms. Nevertheless, they maintained chemosensitivity to a second-line therapy. In elderly B-NHL patients with advanced stage of disease and comorbidity, R-CCOP seems to be safe, feasible and effective. These results confirm and improve in a larger cohort of patients those reported by Zaja, Tulpule and Coiffier in their previous series (see table).

The role of ASCT in AML appears to be appropriate in patients with favorable cytogenetic features whereas allogeneic SCT is appropriate in those with high-risk cytogenetic features. Gemtuzumab ozogamicin (GO), a monoclonal antibody conjugated to the calicheamicin, targets the CD33+ cell surface marker that is expressed on cells in the majority of AML patients. Clinical trials currently underway are investigating the role of GO in consolidation therapy. We hypothesized that GO could have beneficial effects as maintenance therapy after hematopoietic SCT in high-risk patients. Here we report data on 4 AML patients in CR who received 4 doses of GO as maintenance therapy following ASCT. Our approach differs from previous reports in the literature in that, instead of using GO to induce a first remission or re-induce a second remission after relapse, we administered GO to patients while they remained in remission, two months after undergoing ASCT. Patient #1 was a 64 year-old male with 88% CD33 expression at diagnosis. This patient had previously undergone an ASCT using a conditioning regimen of Bu+Cy. He was in second CR following an induction regimen of 2 cycles of fludarabine + cytarabine + idarubicin. Patient #2 was female, aged 67 years and had 90% CD33 expression at diagnosis. She was in first CR following an induction regimen of 2 cycles of etoposide + cytarabine + idarubicin. Patient #3 was a 69-year old male with 95% CD33 expression at diagnosis. He was in first CR following an induction regimen of 2 cycles of fludarabine + cytarabine. Patient #4 was a 59 year-old male with 93% CD33 expression. He was in first CR after a second line treatment with mitoxantrone, cytarabine and etoposide. Histocompatible donors were not available for any of the patients. Three months after attaining CR, all 4 patients received a myeloablative conditioning regimen with B(A)VC, Bu+Cy, Bu+Cy and TBI+Melphalan, respectively, and underwent ASCT. Two months after the ASCT procedure, patients initiated treatment with GO: GO was administered alone for 4 doses with 28 days between doses (two patients received 6 mg/mq for the two first doses and 3 mg/mq for the two last doses; two patients received 3 mg/mq for four doses). All four patients remain alive and in CR at +17, +13, +11and + 5 months. Overall survival at the time of reporting is +35, +15, +13 and +8 months in patients 1, 2, 3 and 4, respectively. There were no cases of grade 3 or 4 liver toxicity and bleeding was not observed in any of the patients. Thrombocytopenia (50,000–100,000 cells/μL) occurred in all four patients and neutropenia (500–1000 cells/μL) in two patients. In conclusion in our small series GO demonstrated good efficacy when administered in fractionated doses as maintenance therapy after ASCT in patients with CD33+ AML in first or second CR. GO showed an acceptable tolerability profile, with no severe hepatotoxicity and no bleeding. Thrombocytopenia occurred in all three patients and in all cases there was a rapid platelet recovery. A GO dose of 3 mg/m2 appeared to be better tolerated than the higher dose (6 mg/m2) and will be used in future studies. If confirmed in a study involving a larger number of patients, our results could support a new therapeutic role for GO, namely as a maintenance therapy for patients in CR following hematopoietic SCT.

The role of ASCT in AML appears to be appropriate in patients with favorable cytogenetic features whereas allogeneic SCT is appropriate in those with high-risk cytogenetic features. Gemtuzumab ozogamicin (GO), a monoclonal antibody conjugated to the calicheamicin, targets the CD33+ cell surface marker that is expressed on cells in the majority of AML patients. Clinical trials currently underway are investigating the role of GO in consolidation therapy. We hypothesized that GO could have beneficial effects as maintenance therapy after hematopoietic SCT in high-risk patients. Here we report data on 4 AML patients in CR who received 4 doses of GO as maintenance therapy following ASCT. Our approach differs from previous reports in the literature in that, instead of using GO to induce a first remission or re-induce a second remission after relapse, we administered GO to patients while they remained in remission, two months after undergoing ASCT. Patient #1 was a 64 year-old male with 88% CD33 expression at diagnosis. This patient had previously undergone an ASCT using a conditioning regimen of Bu+Cy. He was in second CR following an induction regimen of 2 cycles of fludarabine + cytarabine + idarubicin. Patient #2 was female, aged 67 years and had 90% CD33 expression at diagnosis. She was in first CR following an induction regimen of 2 cycles of etoposide + cytarabine + idarubicin. Patient #3 was a 69-year old male with 95% CD33 expression at diagnosis. He was in first CR following an induction regimen of 2 cycles of fludarabine + cytarabine. Patient #4 was a 59 year-old male with 93% CD33 expression. He was in first CR after a second line treatment with mitoxantrone, cytarabine and etoposide. Histocompatible donors were not available for any of the patients. Three months after attaining CR, all 4 patients received a myeloablative conditioning regimen with B(A)VC, Bu+Cy, Bu+Cy and TBI+Melphalan, respectively, and underwent ASCT. Two months after the ASCT procedure, patients initiated treatment with GO: GO was administered alone for 4 doses with 28 days between doses (two patients received 6 mg/mq for the two first doses and 3 mg/mq for the two last doses; two patients received 3 mg/mq for four doses). All four patients remain alive and in CR at +17, +13, +11and + 5 months. Overall survival at the time of reporting is +35, +15, +13 and +8 months in patients 1, 2, 3 and 4, respectively. There were no cases of grade 3 or 4 liver toxicity and bleeding was not observed in any of the patients. Thrombocytopenia (50,000–100,000 cells/μL) occurred in all four patients and neutropenia (500–1000 cells/μL) in two patients. In conclusion in our small series GO demonstrated good efficacy when administered in fractionated doses as maintenance therapy after ASCT in patients with CD33+ AML in first or second CR. GO showed an acceptable tolerability profile, with no severe hepatotoxicity and no bleeding. Thrombocytopenia occurred in all three patients and in all cases there was a rapid platelet recovery. A GO dose of 3 mg/m2appeared to be better tolerated than the higher dose (6 mg/m2) and will be used in future studies. If confirmed in a study involving a larger number of patients, our results could support a new therapeutic role for GO, namely as a maintenance therapy for patients in CR following hematopoietic SCT.

The Lymphomatous Meningitis (LM) is an uncommon event, either as an initial diagnosis and in the course (or as an outcome) of a front line treatment. In the latter cases the LM has a poor prognosis and a median survival of few months in untreated patients. Its occurrence is tightly related to the histology, the response to the therapy and the introduction of a proper prophylaxis. Currently, high doses of Methotrexate (HD-MTX) (3 g/sqm) followed by radiotherapy (WBRT: 50 Gy) represents the elective treatment. The role of the intrathecal therapy (IT-T) isn’t well defined: as a matter of facts, it doesn’t seem more effective than the systemic treatment with HD-MTX and it is burdened by a higher neurotoxicity. Furthermore, more frequent intrathecal administrations, a proper concentration and a prolonged exposition to the drugs are required. Recently, an important role both in the prophylaxis and in the therapy of LM is played by the IT-T of Cytarabine in liposomal formulation (DepoCyte): the slow release from the multivescicular lipidic particles improves the distribution in the liquor, allows a lesser number of IT-T, reduces the undesired effects due to the treatment and increases the compliance of patients. Randomized studies have shown a significant better effectiveness and a reduced toxicity of liposomal formulation treatment with respect to the traditional one. In the present work 9 cases of LM treated with systemic chemotherapy and with DepoCyte (50 mg IT every 15 days x 6 times) are shown. Male/Female ratio is 6/3; average age is 46 years (range 24–78). In all patients neurological symptoms were present; lymphomatous cells were identified in the CSF of 5 patients and Central Nervous System (CNS) localizations were detected by NMR in 7 patients. The 5 CSF-positive cases were heterogeneous, as follows: B-lineage CD10+ ALL meningeal relapse (after two marrow relapses), already undertaken to allogeneic stem cells transplantation, treated only with DepoCyte; Lymphoblastic T-Cell Lymphoma meningeal localization, with mediastinic mass, treated with DepoCyte associated to LSA2L2 Protocol and autologous stem cells tranplantation; DLBCL meningeal localization treated with DepoCyte associated to R-CHOP Protocol; LM at diagnosis in a 78 years old patient with inadequate compliance to systemic therapy, treated with DepoCyte; Mantle Cell Lymphoma meningeal (and systemic) relapse treated with DepoCyte associated to Codox-M Protocol. In patients 1) to 4) the CR was obtained and they are still alive; only the latter patient, namely, case 5), died for disease progression. The remaining 4 CSF-negative cases had been diagnosed as DLBCL (3 at diagnosis and 1 at relapse) CNS solitary localizations. In all cases L-VAMP Protocol (modified with HD-MTX) was associated to IT-T with DepoCyte. With the only exception of the relapsed patient, the remaining 3 patients had a good response to therapy and they are still alive and in CR.Overall, DepoCyte was shown to be mostly effective, well tolerated by all patients and devoid of undesired side effects. The association with various systemic chemotherapy protocols had been demonstrated to be suitable and endowed with synergic effects. Studies with higher number of patients might validate the effectiveness of DepoCyte also in those CSF-negative cases with solitary CNS localization.

The Lymphomatous Meningitis (LM) is an uncommon event, either as an initial diagnosis and in the course (or as an outcome) of a front line treatment. In the latter cases the LM has a poor prognosis and a median survival of few months in untreated patients. Its occurrence is tightly related to the histology, the response to the therapy and the introduction of a proper prophylaxis. Currently, high doses of Methotrexate (HD-MTX) (3 g/sqm) followed by radiotherapy (WBRT: 50 Gy) represents the elective treatment. The role of the intrathecal therapy (IT-T) isn't well defined: as a matter of facts, it doesn't seem more effective than the systemic treatment with HD-MTX and it is burdened by a higher neurotoxicity. Furthermore, more frequent intrathecal administrations, a proper concentration and a prolonged exposition to the drugs are required.

Epidemiological studies indicate that HCV infection prevalence is higher in patients with B-cell non-Hodgkin’s lymphomas (B-NHL) than in general population or in other hematologic malignancies, thus contributing to confirm a possible pathogenetic role for HCV in lymphomagenesis. Such differences are particularly striking in Italian and Japanese populations, where it has been calculated that 5–12% of all B-NHL could be due to HCV. The relationship between HCV and B-NHL is stronger for some sub-types of low-grade B-NHL (immunocytomas and nodal/extranodal marginal zone lymphomas) where, interestingly, anti-viral therapy may induce regression of lymphoma. However, an association with HCV infection has been observed also within more aggressive histotypes, in particular in DBLCL. We evaluated the clinical outcome of 44 patients with DBLCL and concomitant HCV infection, diagnosed at our Institution from 1992 to 2000. These patients represented 19% of all 231 patients with DBLCL we observed throughout the same period. With respect to HCV- DLBCL, HCV+ DBLCL showed some distinctive clinico-pathological features, such as older age (61 vs 44 years, p < 0.03), signs of liver damage (56.8% vs 6.9%, p < 0.01), presence of monoclonal gammopathy, often with no clinically relevant cryoglobulinemic and/or rheumatoid activity (15.9% vs 4.2%, p < 0.05), increased rate of autoimmune disorders (18.1% vs 2.6%, p < 0.02) and extranodal localizations (61.3% vs 32%, p < 0.04), including, in particular, liver, spleen and some very unusual sites, such as esophagous and vagina. First line chemotherapy for HCV+ DBLCL consisted of CHOP/CHOP-like +/-rituximab or PROMACE-CytaBOM regimens. Intensive chemotherapy followed by autologous peripheral blood stem cell transplantation was also performed in two patients. Response rate was 61.3% (69.5% for HCV- DBLCL, p n.s.). Overall survival (OS) at five years was 50% (53.4% for HCV- DBLCL, p n.s.). However, the evidence of increased ALT levels at diagnosis resulted in a worse prognosis, with a five-years OS of only 34% (p < 0.02). High viral load and evidence of active hepatitis or cirrhosis at liver biopsy also were associated with more frequent hepatic failure under treatment and reduced survival. The concomitant administration of R-CHOP chemotherapy plus anti-viral treatment with peg-interferon (0.5-1 mcg/kg s.c., once-a-week) and ribavirin (1000-1200 mg/d p.o.) to four patients with HCV+ DBLCL showed excessive hematological toxicity. After this initial negative experience, we treated HCV+ DBLCL with R-CHOP (6–8 cycles) followed by a three months period of maintenance therapy with peg-interferon plus ribavirin. Such a sequential treatment was effective, better tolerated and resulted in a high rate of complete virus clearance in the first 12 patients so far treated. Thus, we recommend standard treatments as in their HCV- counterparts (including autologous stem cell transplantation) for HCV+ DBLCL patients without liver dysfunction. Monitoring of viral load and liver biopsy appears also to be useful for an appropriate management of these patients. Dose adaptation of chemotherapy and less intensive treatments are required in patients with sign of liver dysfunction. A sequence of standard chemotherapy followed by a short period of antiviral treatment is a feasible approach, requiring, however, a larger number of patients and a longer follow-up to establish its exact role in HCV+ DBLCL patients.

Epidemiological studies indicate that HCV infection prevalence is higher in patients with B-cell non-Hodgkin's lymphomas (B-NHL) than in general population or in other hematologic malignancies, thus contributing to confirm a possible pathogenetic role for HCV in lymphomagenesis. Such differences are particularly striking in Italian and Japanese populations, where it has been calculated that 5–12% of all B-NHL could be due to HCV. The relationship between HCV and B-NHL is stronger for some sub-types of low-grade B-NHL (immunocytomas and nodal/extranodal marginal zone lymphomas) where, interestingly, anti-viral therapy may induce regression of lymphoma. However, an association with HCV infection has been observed also within more aggressive histotypes, in particular in DBLCL. We evaluated the clinical outcome of 44 patients with DBLCL and concomitant HCV infection, diagnosed at our Institution from 1992 to 2000. These patients represented 19% of all 231 patients with DBLCL we observed throughout the same period. With respect to HCV- DLBCL, HCV+ DBLCL showed some distinctive clinico-pathological features, such as older age (61 vs 44 years, p < 0.03), signs of liver damage (56.8% vs 6.9%, p < 0.01), presence of monoclonal gammopathy, often with no clinically relevant cryoglobulinemic and/or rheumatoid activity (15.9% vs 4.2%, p < 0.05), increased rate of autoimmune disorders (18.1% vs 2.6%, p < 0.02) and extranodal localizations (61.3% vs 32%, p < 0.04), including, in particular, liver, spleen and some very unusual sites, such as esophagous and vagina. First line chemotherapy for HCV+ DBLCL consisted of CHOP/CHOP-like +/-rituximab or PROMACE-CytaBOM regimens. Intensive chemotherapy followed by autologous peripheral blood stem cell transplantation was also performed in two patients. Response rate was 61.3% (69.5% for HCV- DBLCL, p n.s.). Overall survival (OS) at five years was 50% (53.4% for HCV- DBLCL, p n.s.). However, the evidence of increased ALT levels at diagnosis resulted in a worse prognosis, with a five-years OS of only 34% (p < 0.02). High viral load and evidence of active hepatitis or cirrhosis at liver biopsy also were associated with more frequent hepatic failure under treatment and reduced survival. The concomitant administration of R-CHOP chemotherapy plus anti-viral treatment with peg-interferon (0.5-1 mcg/kg s.c., once-a-week) and ribavirin (1000-1200 mg/d p.o.) to four patients with HCV+ DBLCL showed excessive hematological toxicity. After this initial negative experience, we treated HCV+ DBLCL with R-CHOP (6–8 cycles) followed by a three months period of maintenance therapy with peg-interferon plus ribavirin. Such a sequential treatment was effective, better tolerated and resulted in a high rate of complete virus clearance in the first 12 patients so far treated. Thus, we recommend standard treatments as in their HCV- counterparts (including autologous stem cell transplantation) for HCV+ DBLCL patients without liver dysfunction. Monitoring of viral load and liver biopsy appears also to be useful for an appropriate management of these patients. Dose adaptation of chemotherapy and less intensive treatments are required in patients with sign of liver dysfunction. A sequence of standard chemotherapy followed by a short period of antiviral treatment is a feasible approach, requiring, however, a larger number of patients and a longer follow-up to establish its exact role in HCV+ DBLCL patients.

Background: We postulated that it is possibile to safely extend the benefit of allografting to relapsed or resistant Hodgkin’s Lymphoma (HL) by combining cytoreduction with high-dose therapy/autologous stem cell transplant (HDT/ASCT) and graft versus HL effect mediated through transplanted donor immune cells with nonmyeloablative allografting (RICT). Methods: Twenty-two patients, 32 years of age (range, 16–39) with heavily pretreated disease were given HDT/ASCT. At a median of 92 days after HDT/ASCT the patients received fludarabine 30 mg/m2/day x 3 days and cyclophosphamide 300 mg/m2/day x 3 days and non-T depleted donor peripheral blood stem cells from HLA-identical siblings. Postgrafting immunosuppression consisted of methotrexate and cyclosporine. Cyclosporine was withdrawn early in patients with mixed chimerism or disease progression. Donor lymphocyte infusions were given to 12 patients with stable mixed chimerism and/or progressive disease. Results: Seventeen patients (77%) achieved full chimerism and 5 patients mixed chimerism. Twelve patients (55%) achieved CR after tandem transplant. The first signs of responsiveness in CR patients began at day ≥60 and the maximal response was achieved on day ≥80. The remitters patients achieved full chimerism and developed acute/chronic GVHD before regression of the disease; moreover, 5 patients achieved CR after DLI. At last follow-up (July 31, 2004), 9 out of 12 CR patients are alive at a median of 1844 days (range, 1092 to 2045). Subsequently, 5 patients relapsed and are now alive on therapy and four patients maintain CR after a median follow-up of 1874 days (range, 1092–2045). Acute GVHD grade ≥ II occurred in 9 patients (40%); chronic GVHD developed in 5 patients (23%), four of them with extensive chronic GVHD requiring further immunosuppressive therapy. Two patients died of GVHD/infections, 1 patient died of extensive chronic GVHD and 7 patients of progressive disease. Conclusions: This tandem auto-allotransplant protocol demonstrated to be highly effective also in advanced resistant Hodgkin’s Lymphoma patients. The exploitation of graft-versus-lymphoma effect is a promising finding

ASCO guidelines recommend the use of granulocyte-colony stimulating factors (G-CSF) as adjuvant agents after autologous peripheral blood stem cell transplantation (PBSCT), for shortening the period of severe neutropenia and reducing the related risk of life-threatening infections. The recently available pegylated formulation of G-CSF (peg-filgrastim) could have some potential advantages in phase of recovery after PBSCT, such as self-regulation mechanisms, particularly useful when neutropenia duration is unforeseeable, possible reduction/standardization of growth factor costs and possibility of more manageable outpatient treatments. We investigated the effects of a single s.c. injection of peg-filgrastim (6 mg) on day 3 in 11 patients (8 with multiple myeloma, MM; 2 with non-Hodgkin’s lymphomas, NHL; 1 with acute myeloid leukemia, AML) planned to receive autologous PBSCT. Mean age was 55 years (range 24–65). In 7 patients PBSCT was performed as consolidation in first complete or partial remission, while 4 patients received the procedure as salvage treatment for chemo-sensitive disease. Conditioning regimens were intermediate/high dose melphalan in MM, BEAM protocol in NHL and TBI plus cyclophosphamide in AML. For comparison, we selected a group of 11 historical controls matched for age, type and status of disease, conditioning regimen, and number of CD34+ stem cells infused, who had received standard daily s.c. administration of G-CSF (300 mcg/d) from day 5 to neutrophil recovery after autologous PBSCT. No adverse events occurred in patients treated with peg-filgrastim. Bone pain was the only side effect referred by one patient. There was no difference between the two groups in terms of median time to hemoglobin recovery, days of febrile neutropenia and number of red cell or platelet transfusions received. However, the median times to neutrophil > 0.5 x 109/L (10 days, range 9–13 vs 12 days , range 11–14, p < 0.000) and platelet > 20 x 109/L (10 days, range 8–15 vs 13 days, range 12–20, p < 0.003) were significantly shorter in peg-filgrastim group. The median number of G-CSF injections in controls was 12 (range 9–20), so that the mean cost of this drug for single patient was 1,764 euros, as compared to 910 euros for patients receiving peg-filgrastim. We conclude that peg-filgrastim and G-CSF have comparable safety and efficacy profiles in patients affected by hematological malignancies who undergo autologous PBSCT. In this specific setting of patients, peg-filgrastim could be cost-effective. Whether peg-filgrastim may be also superior in reducing the periods of neutropenia and thrombocytopenia, requires to be confirmed and further investigated in larger studies.

ASCO guidelines recommend the use of granulocyte-colony stimulating factors (G-CSF) as adjuvant agents after autologous peripheral blood stem cell transplantation (PBSCT), for shortening the period of severe neutropenia and reducing the related risk of life-threatening infections. The recently available pegylated formulation of G-CSF (peg-filgrastim) could have some potential advantages in phase of recovery after PBSCT, such as self-regulation mechanisms, particularly useful when neutropenia duration is unforeseeable, possible reduction/standardization of growth factor costs and possibility of more manageable outpatient treatments. We investigated the effects of a single s.c. injection of peg-filgrastim (6 mg) on day 3 in 11 patients (8 with multiple myeloma, MM; 2 with non-Hodgkin's lymphomas, NHL; 1 with acute myeloid leukemia, AML) planned to receive autologous PBSCT. Mean age was 55 years (range 24–65). In 7 patients PBSCT was performed as consolidation in first complete or partial remission, while 4 patients received the procedure as salvage treatment for chemo-sensitive disease. Conditioning regimens were intermediate/high dose melphalan in MM, BEAM protocol in NHL and TBI plus cyclophosphamide in AML. For comparison, we selected a group of 11 historical controls matched for age, type and status of disease, conditioning regimen, and number of CD34+ stem cells infused, who had received standard daily s.c. administration of G-CSF (300 mcg/d) from day 5 to neutrophil recovery after autologous PBSCT. No adverse events occurred in patients treated with peg-filgrastim. Bone pain was the only side effect referred by one patient. There was no difference between the two groups in terms of median time to hemoglobin recovery, days of febrile neutropenia and number of red cell or platelet transfusions received. However, the median times to neutrophil > 0.5 x 109/L (10 days, range 9–13 vs 12 days , range 11–14, p < 0.000) and platelet > 20 x 109/L (10 days, range 8–15 vs 13 days, range 12–20, p < 0.003) were significantly shorter in peg-filgrastim group. The median number of G-CSF injections in controls was 12 (range 9–20), so that the mean cost of this drug for single patient was 1,764 euros, as compared to 910 euros for patients receiving peg-filgrastim. We conclude that peg-filgrastim and G-CSF have comparable safety and efficacy profiles in patients affected by hematological malignancies who undergo autologous PBSCT. In this specific setting of patients, peg-filgrastim could be cost-effective. Whether peg-filgrastim may be also superior in reducing the periods of neutropenia and thrombocytopenia, requires to be confirmed and further investigated in larger studies.

Background: We postulated that it is possibile to safely extend the benefit of allografting to relapsed or resistant Hodgkin's Lymphoma (HL) by combining cytoreduction with high-dose therapy/autologous stem cell transplant (HDT/ASCT) and graft versus HL effect mediated through transplanted donor immune cells with nonmyeloablative allografting (RICT).