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248 patients with non-Hodgkin lymphomas (NHL) were retrospectively analysed in an attempt to elucidate the risk factors, the prognostic importance and the therapeutic implications of blood involvement. Bone marrow involvement and large spleen were significantly correlated to leukaemic manifestations (P less than 0.0001 and P less than 0.0005, respectively); conversely no correlations were seen with bulky disease and symptoms. Among low-grade malignant lymphomas (LGML) centroblastic-centrocytic follicular and diffuse or diffuse and "CLL" subtypes were mostly associated with blood involvement (31% and 55%, respectively). Among high-grade malignant lymphomas (HGML) lymphoblastic type is more frequently associated with blood involvement (42%) than the other subtypes. Blood involvement was not clearly correlated with the prognosis either in LGML (median survival 39 and 36 months for leukaemic and non-leukaemic patients, respectively) or HGML (median survival 12 and 18 months, respectively), although a shorter survival of leukaemic than non-leukaemic lymphoblastic lymphoma was observed (median survival 8 months versus 14 months, respectively). The poorer response rate to therapy of leukaemic patients (median duration of CR22 and 5 months in LGML and HGML, respectively) as opposed to non-leukaemic patients (median duration of CR 29 and 23 months, respectively) led us to consider an alternative treatment in such patients.

As it has been shown that α-interferon (αIFN) treatment modifies the survival of chronic myeloid leukaemia (CML) patients in comparison with conventional chemotherapy, a new prognostic score was devised with the aim of providing a treatment-adapted risk evaluation. We have tested the new prognostic score (the Euro score) in an independent series of 272 patients less than 56 years old with previously untreated, chronic phase, Philadelphia (Ph)-positive CML who had been assigned prospectively to αIFN treatment between 1989 and 1991. The Sokal score system was used as a reference. The new Euro score predicted the response to αIFN as the Sokal score. The median survival of low-risk, intermediate-risk and high-risk patients was similar using the Euro score (105, 65 and 45 months) and Sokal score (105, 76 and 45 months) but, by multivariate analysis, the Euro was more potent than Sokal for predicting survival time. The new Euro score identified more low-risk cases (59% vs. 48%) and fewer high-risk cases (9% vs. 23%) than the Sokal score. The main differences between the Euro and Sokal scores concerned age (it is more important in the Euro than in Sokal), spleen size and the percentage of myeloblasts in peripheral blood (more important in Sokal than in Euro). We conclude that the new Euro score marks an improvement in the prognostic evaluation of CML treated with αIFN. By comparison with the Sokal score, the Euro was more potent and identified more low-risk patients but left only a small number of cases in the high-risk group.

As it has been shown that alpha-interferon (alphaIFN) treatment modifies the survival of chronic myeloid leukaemia (CML) patients in comparison with conventional chemotherapy, a new prognostic score was devised with the aim of providing a treatment-adapted risk evaluation. We have tested the new prognostic score (the Euro score) in an independent series of 272 patients less than 56 years old with previously untreated, chronic phase, Philadelphia (Ph)-positive CML who had been assigned prospectively to alphaIFN treatment between 1989 and 1991. The Sokal score system was used as a reference. The new Euro score predicted the response to alphaIFN as the Sokal score. The median survival of low-risk, intermediate-risk and high-risk patients was similar using the Euro score (105, 65 and 45 months) and Sokal score (105, 76 and 45 months) but, by multivariate analysis, the Euro was more potent than Sokal for predicting survival time. The new Euro score identified more low-risk cases (59% vs. 48%) and fewer high-risk cases (9% vs. 23%) than the Sokal score. The main differences between the Euro and Sokal scores concerned age (it is more important in the Euro than in Sokal), spleen size and the percentage of myeloblasts in peripheral blood (more important in Sokal than in Euro). We conclude that the new Euro score marks an improvement in the prognostic evaluation of CML treated with alphaIFN. By comparison with the Sokal score, the Euro was more potent and identified more low-risk patients but left only a small number of cases in the high-risk group.

Although a large amount of data is available on the effects of filgrastim (granulocyte colony-stimulating factor [G-CSF]) on the mobilization of stem cells in the circulation, data concerning its effects on bone marrow (BM) harvesting is scarce and controversial. We have designed a randomized trial comparing filgrastim-mobilized peripheral blood stem cell (PBSC) transplantation with filgrastim-primed autologous bone marrow transplantation (ABMT). Fifty-five patients affected by non-Hodgkin's (n = 38) or Hodgkin's (n = 17) lymphoma, selected for autologous transplantation over a 12-month period in a single institution, were randomized 2:1 to undergo BM or PB harvest/collection after priming for 3 days with filgrastim, 16 μg/kg body weight daily subcutaneously. BM priming with G-CSF allowed the harvest of a significantly higher number of mononuclear cells (MNC) (0.53 × 108/kg, range, 0.32 to 1.40), as compared with a historical control of unprimed BM harvests (0.43 × 108 MNC/kg, range, 0.15 to 0.72, P = .001). After high-dose ablative therapy, median time to neutrophil recovery above 0.5 × 109/L was 12 days for BM and 11 days for PB (P = .219); median time to platelet recovery above 20 × 109/L was 13 days for BM and 11 days for PB (P = .242). The same number of red blood cells, platelet transfusions, and posttransplant G-CSF doses were required in the two groups of patients. Less patients (50% v 70%) became febrile in the group transplanted with mobilized PB, but days of fever/patient and days on antibiotics were overlapping. The median time spent in the hospital after reinfusion was 16.5 and 15.5 days after primed BM and primed PB, respectively (P = .134). These data suggest that in patients with lymphoma submitted to autologous transplantation, the reinfusion of filgrastim-primed BM or filgrastim-mobilized PB leads to similar results, with an advantage of only 1 day in the neutrophil recovery and 1 day on the time spent in the hospital in favor of primed PB. Either option can be chosen on the basis of the availability of a surgery room or cell separator facilities and considering the patients' characteristics and wishes.

PURPOSE To evaluate, in a prospective multicentric study, the efficacy of a conventional salvage chemotherapy (dexamethasone, cisplatin, and cytarabine [DHAP]) versus high-dose chemotherapy (carmustine, etoposide, cytarabine, and cyclophosphamide [BEAC]) followed by autologous bone marrow transplantation (ABMT) in patients with aggressive non-Hodgkin's lymphoma (NHL) in clinical partial response (PR) after two thirds of a conventional front-line therapy. PATIENTS AND METHODS From August 1988 to August 1991, 286 patients with aggressive NHL were randomized in seven Italian institutions to receive fluorouracil, methotrexate, cytarabine, cyclophosphamide, doxorubicin, vincristine, and prednisone (F-MACHOP) or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) as front-line therapy. Of the 286 patients enrolled onto the trial, 77 (27%) were considered in PR after two thirds of the front-line therapy, and 49 of 77 (64%) were randomized: 27 to receive DHAP chemotherapy and 22 to receive BEAC followed by ABMT. RESULTS The response after second-line treatment was as follows: in the DHAP group, four patients (15%) achieved a complete remission (CR), 12 (44%) remained in stable PR, and 11 (41%) showed progressive disease; in the ABMT group, three patients (14%) obtained a CR, 18 (82%) obtained a stable PR, and one (4%) progressed, with an overall response (CR + stable PR) of 59% and 96% (P < .001) in the DHAP and ABMT groups, respectively. The overall survival was 59% versus 73% and the progression-free survival (PFS) was 52% versus 73% in the DHAP and ABMT groups, respectively (P, not significant). The toxicity was mild, particularly in the ABMT group, and no treatment-related deaths occurred in either group. CONCLUSION Because of the small number of patients randomized, we were unable to determine whether ABMT or a standard salvage regimen (DHAP) is superior for PR patients. However, we confirmed that myeloablative treatment is a safe and well-tolerated procedure in this category of patients and this may enable us to evaluate its role as part of a front-line treatment in poor-risk NHL patients.

BACKGROUND: A risk score for invasive mold disease (IMD) in patients with hematological malignancies could facilitate patient screening and improve the targeted use of antifungal prophylaxis. METHODS: We retrospectively analyzed 1,709 hospital admissions of 840 patients with hematological malignancies (2005-2008) to collect data on 17 epidemiological and treatment-related risk factors for IMD. Multivariate regression was used to develop a weighted risk score based on independent risk factors associated with proven or probable IMD, which was prospectively validated during 1,746 hospital admissions of 855 patients from 2009-2012. RESULTS: Of the 17 candidate variables analyzed, 11 correlated with IMD by univariate analysis, but only 4 risk factors (neutropenia, lymphocytopenia or lymphocyte dysfunction in allogeneic hematopoietic stem cell transplant recipients, malignancy status, and prior IMD) were retained in the final multivariate model, resulting in a weighted risk score 0-13. A risk score of < 6 discriminated patients with low (< 1%) versus higher incidence rates (> 5%) of IMD, with a negative predictive value (NPV) of 0.99, (95% CI 0.98-0.99). During 2009-2012, patients with a calculated risk score at admission of < 6 had significantly lower 90-day incidence rates of IMD compared to patients with scores > 6 (0.9% vs. 10.6%, P

The JAK2(V617F) mutation occurs in 50% of patients with essential thrombocythemia (ET). We investigated the correlation between the JAK2(V617F) mutation and clinical and laboratory characteristics, thrombohemorrhagic risk and incidence of disease evolution in 275 patients with ET followed for a median follow-up of 7 years. JAK2(V617F) mutation was detected in 175 patients (64%), of whom 173 were heterozygous. Patients with the mutation were older and displayed higher hemoglobin and hematocrit levels, but lower platelet count. Cytotoxic treatment requirement was similar in the two groups, but patients with the mutation showed better responses. Incidence of thrombosis and disease evolution was comparable. JAK2 mutational status assessment was valuable to distinguish two populations of patients with ET, showing distinctive hematologic and clinical features.

Abstract 351 Introduction A phase III study of melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) incorporating thalidomide (T) and dexamethasone (D) with or without the addition of bortezomib (V) as first-line therapy for younger (≤65 years) patients (pts) with newly diagnosed multiple myeloma (MM) is currently being conducted by the Italian Myeloma Network GIMEMA. Patients and Methods By study design, pts were random assigned to receive three 21-d cycles of either bortezomib-thalidomide-dexamethasone (VTD) (V, 1.3 mg/m2 twice-weekly; T, 200 mg/d through d 1 to 63; D, 320 mg/cycle) or thalidomide-dexamethasone (TD) (both drugs at the same dose and schedule than in VTD) as induction therapy in preparation for ASCTs. Two 35-d cycles of either VTD or TD were given as consolidation therapy following ASCTs (V, 1.3 mg/m2 once-weekly; T, 100 mg/d through d 1 to 70; D, 320 mg/cycle). Primary study end point was the rate of high-quality responses [immunofixation negative complete response (CR) and ≥very good partial response (VGPR)] to induction therapy. Secondary study end points included response to, and toxicity of, subsequent treatment phases (including first and second ASCTs, and consolidation therapy), progression-free survival (PFS) and overall survival (OS). Analyses were intent to treat. All the 474 pts were evaluated for response to, and toxicity of, induction therapy. Responses reported by study investigators were centrally reassessed to confirm CR and VGPR; pts reported as complete responders but in whom bone marrow aspirate was not evaluable or not performed were reassessed as in VGPR. The VGPR category included the subcategories of near CR and VGPR. Results The study was closed to pts accrual after a total of 480 pts were enrolled; of these, 6 failed inclusion criteria and the remaining 474 were randomized to the VTD (n=236) or TD (n=238) arm. The mean total dose of V received in induction therapy was 14.7 mg (or 94% of that planned). Grade 3 peripheral neuropathy (PN) and skin rash (SR) were reported more frequently with VTD induction therapy than with TD (PN: 9.7% vs 2.1%, respectively; P Conclusions Incorporation of VTD into double ASCT for newly diagnosed MM resulted in a significant improvement in clinical outcomes (CR, ≥VGPR, PFS) in comparison with TD and double autotransplantation. Superior benefit with VTD and double ASCT in comparison with the control group was maintained in pts at high risk of progression or death, including those with t(4;14) and/or del(17p). Disclosures: Cavo: Celgene: Honoraria; Ortho Biotech, Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Honoraria; Novartis: Honoraria.

Abstract 349 We report here on the final analysis of the multicenter phase II “Bologna 2002” study which incorporated thal-dex into double ASCT with high-dose melphalan (200 mg/m2) as front-line therapy for younger patients with symptomatic multiple myeloma (MM). By study design, thal (200 mg/day) and pulsed low-dose dex (160 mg/month, with two added 4-day courses on the first and third cycle of induction therapy) were administered from the outset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 357 patients who were followed for a median of 43 months. Their median age was 57 years, 86% had advanced disease stage. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities (FISH) on CD138+ bone marrow plasma cells, including del(13q) (45%), t(4;14) (14%) and del(17p) (6%). The rate of at least VGPR increased from 31% after thal-dex induction therapy to 60% after the second ASCT. The final CR rate was 33% for all the patients and 44% for those who actually received pre planned double ASCT. Median TTP and PFS were 68 and 47 months, respectively, with 5-year projected rates of 45% and 33%. The 5-year projected OS rate was 65%. TRM after the first and second ASCT was 0.5% and 2%, respectively. Median OS after relapse or progression was 30 months, suggesting that short-term thal exposure had no adverse influence on response to salvage therapies. The quality of response following ASCT(s) influenced clinical outcomes. In particular, patients achieving CR had significantly longer PFS and OS than patients in VGPR (PFS: median 68 vs 48 months, respectively, P=0.04; 5-year projected OS 84% vs 72%, respectively, P=0.02). Similarly, patients in VGPR had better outcomes compared with patients achieving PR (P=0.02 and 0.04 for PFS and OS comparisons, respectively). In a multivariate analysis, best response (at least VGPR) ever achieved and low beta2-m were the most important variables significantly extending TTP (P=0.04), PFS (P=0.000) and OS (P=0.003). Additional variables predicting for prolonged PFS were the absence of del(13q) (P=0.002) and del(17p) with or without t(4;14)(P=0.03). OS was favourably influenced also by IgG isotype (P=0.04) and absence of high-risk cytogenetic abnormalities [del (17p) +/- t(4;14)(P=0.03)]. A case match comparison of 135 patients enrolled in “Bologna 2002” study with an equal number of pair mates included in the previous “Bologna 96” study of double ASCT without thal confirmed the benefits from the addition of thal-dex to double autotransplantation in terms of rate (P=0.001) and duration (p Disclosures: Off Label Use: Thalidomide was incorporated into up-front treatment for patients with newly diagnosed multiple myeloma.

Cytotoxic agents like Hydroxyurea, Busulfan and Interferon-alpha are to date the most commonly used therapeutic approaches in Essential Thrombocythemia (ET). However, few data on the efficacy and safety of these agents in the long-term are currently available. We report a retrospective analysis of the long-term outcome of 386 consecutive ET patients, followed at single Institution for a median follow-up of 9.5 years (range, 3-28.5). Cytoreductive therapy was administered to 338 patients (88%), obtaining a response in 86% of cases. Forty-five patients (12%) experienced a thrombosis. Among baseline characteristics, only history of vascular events prior to ET diagnosis predicted a higher incidence of thrombosis. Evolution in acute leukemia/myelofibrosis occurred in 6 (1,5%) and 20 (5%) patients, and was significantly higher in patients receiving sequential cytotoxic agents. Overall survival was 38% at 19 years and was poorer for patients older than 60 years, with higher leukocytes count (>15 x 10(9)/L), hypertension and mellitus diabetes at ET diagnosis and for patients experiencing a thrombotic event during follow-up. Cytoreductive therapy was effective in decreasing platelet number with negligible toxicity; however, thrombocytosis control did not reduce the incidence of thrombosis and, for patients who received sequential therapies, the probability of disease evolution was higher and survival was poorer.

Purpose To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). Patients and Methods One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide. Results On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events. Conclusion In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.

A simple prognostic classification of Ph+ chronic myeloid leukemia (CML) was proposed in 1984 by an international study Group [23] and is now widely used for clinical purposes. That study was retrospective, and was based on disease features at diagnosis. To test prospectively and to check the value of the classification, and to investigate if additional information on the early course of leukemia can help in refining the prognosis, 505 Ph+, nonblastic and nontransplanted patients first registered between 1984 and 1986 were followed up to June 1990. It was found that the prognostic formulation predicted survival in that series exactly the same way as in the original series (median survival: > 60 months for low-risk patients, 46 months for intermediate-risk patients, and 32 months for high-risk ones). It was also found that several objective or subjective assessments of disease course during the first 8 months after diagnosis were significantly related to survival length within any risk group. This study provides full confirmation of Sokal's international prognostic classification, and shows that the definition of prognosis can be improved some months after diagnosis by taking into account the course of the disease and the response to therapy. These conclusions apply to patients receiving conventional treatment. The course of Ph+ chronic myeloid leukemia (CML) is rigidly programmed to progress to an acute phase, which is called blastic metamorphosis (BM) and which can develop either suddenly (blastic crisis) or by a slow progression (accelerated phase) [7,24,29]. In all recent series, 2-year survival ranged between 65% and 80%, median survival was slightly shorter than 4 years, and the proportion of patients who were still alive after 10 years was less than 10% [24,29]. However, a number of prognostic variables were identified [2,8,9,12,15,16,19,23, 28] and a prognostic formulation that was claborated by an international study [23] was shown to provide a reliable estimate of survival length and is currently used for that purpose. The value of that formulation, and the formulation itself, require periodical controls and revisions. For that purpose, the Italian Cooperative Study Group on CML registered and followed up all CML patients who were first seen between 1984 and 1986. A very preliminary analysis of that cohort of patients has already been performed, but it was limited to the first 2 years after diagnosis [10]. This report extends prior findings, confirming the validity of the formula up to the 5th year after diagnosis, and shows that the definition of prognosis can be significantly improved by taking into account dynamic clements which reflect the course of the disease and the response to conventional treatment during the first 8 months after diagnosis.

Thirty-seven patients affected by polycythaemia rubra vera (PRV) and with at least one additional thrombotic risk factor (overt vascular disease, diabetes mellitus, treated hypertension, smoking habit

Purpose We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). Patients and Methods A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B). Results As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70). Conclusion In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.

We observed a significant increase of Pseudomonas aeruginosa bacteremias during 2002. Eighty-five microbiological samples were taken from different potential sources of infection. Twenty-nine out of 46 specimens obtained from water taps, shower heads and siphons tested positive for Pseudomonas aeruginosa. Weekly pharyngeal and rectal swabs in high risk patients, use of tap water after running the tap for at least 5 minutes and use of weekly disposable sterile filters in all taps and showers resulted in a significant decrease in Pseudomonas aeruginosa bacteremias. Moreover, we observed a significant reduction in Pseudomonas aeruginosa-positive surveillance cultures after implementation of these measures.

Summary Fludarabine plus cytarabine (Ara-C) and idarubicin (FLAI) is an effective and well-tolerated induction regimen for the treatment of acute myeloid leukaemia (AML). This phase III trial compared the efficacy and toxicity of FLAI versus idarubicin plus Ara-C and etoposide (ICE) in 112 newly diagnosed AML patients

Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Flow cytometric expression of bcl-2 protein was analyzed in 90 newly diagnosed acute myeloblastic leukemia (AML) patients using an anti-bcl-2 monoclonal antibody by direct immunofluorescence technique and results were correlated with FAB cytotype, CD34 expression and clinical outcome. Bcl-2 was expressed in all AML cases with different intensity. The mean fluorescence index (MFI), expressed as the ratio of sample mean channel:control mean channel, ranged from 3.0 to 39.5 with a median value of 14. The MFI was significantly higher (P = 0.01) in M0 (20.9) and M1 (18.3) than in M2 (11.7), M3 (12.4), M4 (11.8) and M5 (9.5) cytotypes. In addition, bcl-2 MFI significantly correlated both with CD34 positivity (P = 0.001) and with CD34 MFI (P = 0.01), being CD34 antigen expressed in 65% of patients with a bcl-2 MFI14, and only in 35% of AML cases with a bcl-2 MFI14. When bcl-2 intensity expression was correlated with complete remission (CR) rate, a higher MFI was associated with a low CR rate after standard intensive chemotherapy. In particular, CR was achieved in 86% of patients with a bcl-2 MFI14, but only in 57% of patients with a MFI14 (P = 0.008). A further decrease of CR rate to 41% was observed in patients in whom a higher bcl-2 MFI was coupled with the presence of CD34 antigen on their blasts. By statistical analysis we also demonstrated that both bcl-2 high MFI (14) and CD34 expression are independent prognostic factors for achieving CR in AML. These data raise the hypothesis that high values of bcl-2 may confer on myeloid blasts a higher resistance to standard chemotherapy. However, identification of patients with high expression of bcl-2 may be important for a different therapeutic approach.

Abstract 594 Survival of patients with multiple myeloma (MM) has been extended with the introduction of autologous stem cell transplantation (ASCT). More recently, availability of highly effective novel agents has further improved patient outcomes. However, it is still the matter of debate whether a proportion of patients treated with ASCT can enjoy a long term survival, while sustaining prolonged high quality response. To address this issue and to identify those variables which were related to long-term survival, we performed a post-hoc analysis of two large prospective clinical trials of ASCT in newly diagnosed MM patients, the first one comparing single versus double ASCT and the second one incorporating thalidomide-dexamethasone (TD) into double ASCT. A total of 321 patients were randomly assigned in the first study to receive either a single or double ASCT, as previously described (Cavo M et al, JCO 2007). Three hundred and fifty seven patients were enrolled in the subsequent multicenter phase 2 study incorporating TD from the outset until the second ASCT; details of the protocol were previously reported (Cavo et al, J. Clin. Oncol 2009). Results were updated as of 30 March 2012 and compared with those previously reported. All the analyses were performed on an intention-to-treat basis. After a median follow-up of 61 months for the entire treatment population of the first study, PFS remained significantly longer with tandem versus single ASCT (median 37 vs 25 months, P= 0.012), while OS was similar in the two groups (median 71 vs 67 months). 47% and 33% of the patients in the double and single ASCT group achieved a CR+nCR (P= 0.008). Overall, in 24% and 11% of the patients, CR+nCR was sustained for more than 5 and 10 years, respectively. In a multivariate Cox regression analysis, best response (CR+nCR) ever achieved was the most important variable significantly extending PFS (P= 0.003) and OS (P=0.050); random assignment to double ASCT was an additional variable predicting for prolonged PFS(P= 0.026). After a median follow-up of 84 months from starting TD in the second study, median values of PFS and OS were 47.2 and 109.6 months, respectively. The final rate of CR+nCR was 34%, which was maintained for a median of 53 months. Overall, in 42.1% and 9.1% of the patients CR+nCR was sustained for more than 5 and 8 years, respectively. On multivariate analysis, failure to ever achieve at least CR+nCR, low Hb, high β2-m and t(4;14)±del(17p) were found to be independent variables predicting for poorer outcomes. In particular, a shorter OS was seen for patients ever lacking high-quality responses (HR: 0.35, 0.23–0.54, p Overall, 23% and 20% of patients in the first and second study were alive over 10 or 8 years, respectively (long-term survivors). Median PFS of long-term survivors in the 2 studies were 74 and 87.7 months, respectively, versus 25 and 37 months for the rest of the population (P= 0.0000). Median duration of CR+nCR were 70 and 78 months in the long-term survivors group for the first and second study, respectively, in comparison with 21 and 49 months in the remaining patients (P In conclusion, although the comparison between TD incorporated into ASCT and ASCT without thalidomide was not directly addressed by this analysis, TD + ASCT was associated with extended PFS and OS. Approximately 20% of the patients undergoing up-front ASCT can achieve long term survival (8–10 years from start of treatment), with 33% of them remaining relapse free. Attainment of sustained high-quality responses was the leading independent variable predicting for long-term OS. Prolonged survival after relapse was a contributing factor to long-term OS. Disclosures: Off Label Use: One of the 2 protocols discussed includes the use of thalidomide as induction prior to ASCT.

Aims and background Although initial treatment of Hodgkin's disease induces a complete remission in most patients, approximately 50% of patients with advanced disease will not achieve a complete remission or will relapse following the first complete remission. Patients and methods Twenty-three patients with relapsed/resistant Hodgkin's disease, observed between January 1991 and October 1993, underwent CEP combination chemotherapy (CCNU, etoposide, prednimustine). All patients had previously received MOPP and ABVD regimens, in combination at diagnosis or sequentially (at diagnosis and at the first relapse). Results Thirteen (56%) patients achieved complete responses and 4 (18%) had partial responses. Two partial responders obtained a complete remission after a successive autologous bone marrow transplantation. The complete remission was not influenced by the timing of MOPP and ABVD treatments, presence of extranodal involvement or presence of bulky disease, but was affected by the presence of a primary disease refractory to the first standard programs. All the complete responders but 2 were alive and relapse-free at a median follow-up of 15 months; no major toxic effects were recorded. Conclusions These data suggest, as did those of other studies, that CEP is an effective regimen in patients with Hodgkin's disease in first or second relapse, also to reduce the tumor burden and to determine chemosensitivity before contingent bone marrow or peripheral blood stem cell support.

In view of studies showing that interferon alfa was effective treatment for chronic myeloid leukemia and that it prolonged survival, we organized a prospective, controlled comparative study of this treatment.We compared recombinant interferon alfa-2a with conventional chemotherapy (hydroxyurea or busulfan) in a trial designed to have a power of 80 percent to detect a difference of 20 percent in median survival between the group given interferon and the group given conventional chemotherapy. Between 1986 and 1988, 322 patients with previously untreated or minimally treated Philadelphia chromosome-positive chronic myeloid leukemia were randomly assigned to treatment with either interferon alfa-2a (218 patients) or conventional chemotherapy (104 patients).The rate of karyotypic response (defined as33 percent of metaphases negative for the Philadelphia chromosome) was 30 percent in the interferon group and 5 percent in the conventional-chemotherapy group (P0.001). The time to progression from the chronic phase of leukemia to an accelerated or a blastic phase was longer in the interferon group than in the conventional-chemotherapy group (median,72 vs. 45 months; P0.001), as was survival (median, 72 vs. 52 months; 6-year survival, 50 percent vs. 29 percent; P = 0.002 for both comparisons). There was one treatment-related death in each group. Treatment was discontinued because of side effects (mainly influenza-like, gastrointestinal, or neurologic symptoms) in 35 patients given interferon alfa-2a (16 percent). The cost of interferon treatment was 200 times that of the conventional treatment.During long-term treatment of Philadelphia chromosome-positive chronic myeloid leukemia, interferon alfa-2a induced more karyotypic responses than conventional chemotherapy, delayed disease progression longer, and prolonged overall survival more.

PURPOSE Following irradiation alone, secondary acute nonlymphocytic leukemia (ANLL) is uncommon; following chemotherapy alone, the risk is increased, but not as much as when combined modality treatments are used. Because ANLL seems more likely to occur in splenectomized patients, attention is focused on an unexpected association between splenectomy and the risk of secondary leukemia. PATIENTS AND METHODS The risk of ANLL was assessed in 503 patients with Hodgkin's disease (HD) homogeneously treated with combined modality therapy (mechlorethamine, vincristine, procarbazine, and prednisone [MOPP] plus radiotherapy). These patients were diagnosed from 1970 through 1984 and monitored until June 1991. RESULTS ANLL was observed in one of 145 (0.69%) patients not splenectomized and in 21 of 358 (5.86%) splenectomized patients, demonstrating a significantly higher frequency of ANLL in the group of patients who underwent splenectomy. The group of patients who developed ANLL received a statistically greater number of MOPP courses than did the group not developing ANLL. ANLL was statistically more frequent in those patients who received more than four cycles of MOPP. Sex, symptoms, extent of radiotherapy, splenectomy, age, and number of MOPP courses were assessed for their impact on ANLL incidence by multivariate analysis. CONCLUSION Cox's proportional hazards regression showed that splenectomy and, as previously described by others, the number of courses of MOPP are prognostic factors that increase the risk of secondary ANLL in HD patients treated with combined modality therapy. These data raise interesting questions regarding the possible role of the spleen in leukemia development.

Thirty-seven patients with stage I-II Hodgkin's disease and massive mediastinal involvement, observed between June 1981 and November 1989, underwent combined modality treatment. This treatment included: 3 cycles of mechlorethamine, vincristine, procarbazine, and prednisone followed by mantle-field irradiation, and subsequently by 3 additional cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine. Thirty-five (95%) patients achieved complete responses and only 2 (5%) had partial responses. All the complete responders are living and relapse-free at a median follow-up of 62 months; no major toxic reactions were recorded. These data suggest, as did those of other studies, that combined modality therapy is superior to either radiotherapy or chemotherapy alone for patients in stage I-II with bulky disease, especially in the mediastinum. In fact, in these particular patients, if adequately treated with a combination of chemotherapy and radiotherapy, the role of massive mediastinal involvement as a poor prognostic factor appears to be less significant.

Invasive fungal infections, particularly invasive aspergillosis (IA), are frequent complications in immunocompromised patients. The identification of risk factors for IA is crucial to select patients who will benefit from different antifungal treatment. Retrospectively, we studied 1,194 hospitalizations registered at our Institution between March 2005 and December 2007, involving 618 patients affected by haematological malignancies (acute leukemia 34%, lymphoma 34%, multiple myeloma 24%, chronic myeloid leukemia 5%, severe aplastic anemia 1.5%, chronic lymphocytic leukemia 1.5%), with the purpose of developing a risk score able to stratify patients in categories at different risk for IA. Every febrile episode and every hospitalization without febrile episodes were recorded as single “phase”, for a total number of 1,409 “phases”. In 53% of the phases, the haematological malignancy was fully active (first presentation or resistant disease), and the main treatments administrated were: induction chemotherapy (18%), consolidation chemotherapy (20%), salvage chemotherapy (15%), HSCT in 33% (autologous: 21%; allogeneic: 12%). In 13% of the hospitalizations, patients did not receive chemotherapy but supportive cares. Seventeen variables were assessed as risk factors for IA according to literature data and to local clinical practice (age, smoking habit, type of job, previous IA, prolonged steroids treatment, diabetes, type of haematological malignancy, disease staus, type of treatment, prolonged neutropenia and lymphocytopenia, acute or chronic GvHD, CMV infection, mucositis, presence or absence of HEPA filter, proximity of building sites to the Haematology Unit) receiving a score ranging from 0 to 2. Summing the weighted points assigned to each variable, a total score (TSCORE08) was calculated for each phase and allowed to empirically identify 3 groups of patients at low (1 to 8), intermediate (8.5 to 11.5), and high (12 to 17) risk for IA, and was significantly higher in patients with IA (p < 0.001). Nine variables resulted to correlated significantly with IA in univariate analysis and were entered into the logistic regression analysis and 4 of them (type of job, lymphocytopenia, disease status, prolonged severe neutropenia) maintained their prognostic significance, allowing to derive, for each phase, a new score (BoSCORE08), which was also significantly higher in patients with IA (p < 0.001). The Areas Under the Curve derived from the TSCORE08 and the BoSCORE08 were equivalent, but the BoSCORE08 significantly reduced the number of variables taken into consideration. Adopting 5 as cut-off value for BoSCORE08, the model showed a high Negative Predictive value, a sensitivity of 0.950 (38/40) and a specificity of 0.545 (623/1,369), with a diagnostic Odds Ratio of around 22, which indicates that the risk of experiencing an IA in a patient with high BoSCORE08 was around 22 times higher than that of a patient with a low BoSCORE08. In conclusion, BoSCORE08 may contribute to optimize the management of patients at high risk for IA, improving the outcome, reducing the toxicity and the costs related to the use of antifungal agents in patients with haematological malignancies.

The phase II “Bologna 2002” clinical study incorporated thalidomide-dexamethasone (thal-dex) into double ASCT with melphalan (200 mg/m2) as frontline therapy for patients with symptomatic multiple myeloma (MM) and less than 65 years of age. By study design, thal (200 mg/d) and dex (40 mg/d x 4d every month, with two added courses on the 1st and 3rd month of therapy) were administered from the outset until the second ASCT. An analysis was performed on 311 consecutive patients who entered the study from January 2002 to March 2006 and were followed for a median of 32 months. On an intention-to-treat (ITT) basis, the ≥ very good partial response (VGPR) rate increased from 29% after 4 months of primary induction therapy with thal-dex to 63% after the second ASCT. Transplantation-related mortality after first and second ASCT was 1% and 3%, respectively. Median durations of relapse-free survival (RFS) and event-free survival (EFS) were 52 and 42 months, respectively. The 5-year projected overall survival (OS) rate was 70%. A case-match comparison of 135 of these patients with an equal number of pair mates who entered the “Bologna 96” study and were randomly assigned to receive double ASCT without thal showed significant benefit from incorporation of thal into double ASCT in terms of increased ≥VGPR rate (68% vs 49%, respectively; P=0.001) and extended RFS (54% vs 32% at 5 years; P=0.005) and EFS (median: 52 vs 33 months; P=0.01). All 311 patients were screened on purified CD138+ bone marrow plasma cells for the presence at diagnosis of chromosome 13 alterations [del(13)] (47% of cases) and t(4;14) (13% of cases). In a logistic regression analysis, neither del(13) nor t(4;14) adversely influenced response (≥VGPR) to primary induction therapy with thal-dex. At the opposite, both absence of del(13) (P=0.001) and low beta2- microglobulin (beta2-m) levels (P=0.007) were significantly related to attainment of ≥VGPR after the second ASCT. In a multivariate analysis of all 311 patients, the most important variable significantly extending time to progression (TTP), EFS and OS was the absence of del(13) (P=0.001, P=0.001 and P=0.007, respectively), along with attainment of ≥VGPR after the second ASCT. OS was also significantly influenced by both beta2-m (P=0.044) and hemoglobin (Hb) concentration (P=0.05), whereas platelet count was an additional prognostic factor for TTP (P=0.025). In conclusion, in comparison with double ASCT, incorporation of thal into double ASCT as up-front therapy for MM significantly improved the response rate (≥ VGPR), RFS and EFS, without adversely affecting postrelapse OS. The presence of del(13) by FISH analysis was the most important and independent variable adversely influencing attainment of ≥ VGPR, EFS and OS following thal-dex and double ASCT.

Induction treatment of acute myeloid leukemia (AML) is conventionally based on regimens containing cytarabine (Ara-C), one anthracycline and, sometimes, a third drug, such as etoposide. Primary P-glycoprotein (Pgp) overexpression is the most important mechanism of multidrug resistance (MDR) in AML cells and it is almost always associated with less response to treatment. To deal with this problem, in 1997, we started a treatment program with a regimen including Fludarabine (FLUDA) for the induction of newly diagnosed AML patients. FLUDA showed to be toxic against the MDR cells, in vitro, and able to enhance Ara-C cytotoxicity by increasing cell concentration of Ara-C 5′ triphosphate and inhibiting DNA repair. Between 1997 and 2004, 110 newly diagnosed AML patients aged less than 60 years were induced with FLAI (Fludarabine 25 mg/sqm/day days 1–5, Ara-C 2 gr/sqm/day days 1–5, Idarubicine 10 mg/sqm/day days 1, 3, 5) in the context of three consecutive prospective multicentric trials. At diagnosis, all the patients were assessed for the Pgp expression by an indirect immunofluorescence method with the anti-p170 monoclonal antibody MRK-16. The results were expressed as the mean fluorescence index (MFI) and patients with a MFI > 6 were setted as MDR+ve. We correlated the Pgp-expression, with the response to the induction. Interestingly, the Pgp+ve (MFI > 6) patients treated with FLAI entered CR as well as the Pgp-ve (MFI < 6). Twenty-four out of 39 Pgp+ve patients (61%) and 54 out of 71 Pgp-ve patients (76%) achieved a CR after a single induction course of FLAI (p= 0.1). This observation strongly supported the original hypothesis that fludarabine could play a favourable role against MDR+ve cells. In order to validate this finding we compared the results obtained in an hystorical group of 136 newly diagnosed AML patients younger than 60 years treated with a non-fludarabine containing regimen AI (Ara-C 200 mg/sqm/day c.i. days 1 - 7, Idarubicine 10 mg/sqm/day days 1, 3, 5). In the non-fludarabine group, 22 out of 69 Pgp+ve patients (32%) and 42 out of 67 Pgp-ve patients (63%) achieved a CR after one course of the induction therapy. This difference was stastically significant (p= 0.0006). Based on these observations, we decided to conduct a match pair study to confirm the superiority of FLAI for overcoming the primary multidrug resistance Pgp-mediated in AML.

Essential Thrombocythemia (ET) is a myeloproliferative disorder associated with persistent thrombocytosis. The main clinical features are recurrent thrombotic and/or hemorrhagic events, involving both the arterial and venous systems. Data concerning the role of platelet-lowering agents to prevent thrombotic and hemorrhagic events are not conclusive, despite the risk associated to the use of some of them as hydroxyurea (HU) or alkylating agents like busulfan (BU), to induce a leukemic transformation or solid malignancy. We report here our experience, on 205 (M 78, F 127) consecutive ET patients (pts) referred to our Institute between January 1977 and December 2003, with a median follow-up of 76 months (4–318). Median age at diagnosis was 66 (15–91) years; median platelet (PLT) number was 780 (465–3700) x109/L. One hundred and ninety-five pts (95%) were considered at high risk for thrombosis. One hundred and eighty of them (92.3%) were treated with platelet-lowering agents: HU (82 pts), BU (39 pts), HU+BU (37 pts), IFNa (6 pts), HU+IFNa (10 pts), BU+IFNa (2 pts) or HU+BU+IFNa (4 pts). In 30/180 (16.7%) and 124/180 (68.9%) pts the treatments were able to maintain the PLT number

Although in the last years new insights have been gained into the biology of multiple myeloma (MM), therapeutic progress has been modest since the introduction of alkylating agents (usually melphalan and cyclophosphamide) nearly three decades ago. With few exceptions, a large number of clinical trials exploring the use of alternating or sequential drug combinations have failed to show any survival advantage over the standard association of melphalan and steroids (MP), which remains the cornerstone of treatment of MM in community practice. More recently, important advances in the management of MM have included the recognition that i) the use of high-dose glucocorticoids, eventually combined with 4-day continuous infusions of vincristine and doxorubicin (VAD regimen), is highly effective, even in alkylating agent-resistant/relapsed MM, and ii) recombinant α-2b interferon (IFN), may be a useful tool either as part of the induction treatment or as maintenance therapy for responsive patients with stable diseas...

Sixty-four adult patients with lymphoblasts lymphoma (LB) identified according to Kiel Classification were analyzed retrospectively. Three distinct clinical presentations were identified: prevalent abdominal disease (29 pts = 45.3%), prevalent mediastinal disease (14 pts = 21.9%) and prevalent superficial node involvement (21 pts = 32.8%). On histological grounds, the patients with abdominal disease were mainly associated to "Burkitt like" cell lymphoma (55%); patients with mediastinal disease to convoluted cell type (58%); and those with superficial node disease to unclassified cell type (48%). Immunological studies showed a significant correlation between mediastinal disease and T phenotype (P = 0.0011), abdominal disease and B phenotype (P = 0.00042), and between superficial node disease and non-B non-T phenotype (P = 0.00024). Survival was independent of the type of clinical presentation and protocol employed but was correlated with the stage (P less than 0.0005), symptoms (P less than 0.025), bulky disease (P less than 0.025) and bone marrow involvement (P less than 0.025). Furthermore the response to therapy was strongly correlated with prognosis (P less than 0.0001) with 34.5 months median survival for complete responders, 9 months for partial responders, and 3 months for non-responders. Four patients underwent bone marrow transplantation (three autologous and one allogeneic BMT in a patient in leukemic phase); three of them are still in CR (18, 22, and 27 months from the transplant) while one patient had an early relapse and died 3 months later.

Twelve patients with lymphocytic lymphoma (L.L.), and 9 patients with histiocytic lymphoma (H.L.), stage III and IV, were treated as outpatients with combination chemotherapy including six courses of cyclophosphamide (Endoxan), Methotrexate, and vincristine (M.E.V. regimen). Marrow depression and side-effects were moderate. In the 12 patients with L.L., there were 6 complete remissions (C.R.), 3 incomplete remission (I.R.), and 3 partial failures (P.F.). In the 9 patients with H.L., there were 7 C.R., 1 I.R. and 1 P.F. Median survival from the end of the therapy is 7 + mos. for the L.L. patients, and 10 + mos. for H.L. patients, all patients being alive but one.

Five hundred and seven patients with Hodgkin's lymphoma (HL), forming the basis of our 18 years experience, are retrospectively analyzed. Four therapeutic periods are recognizable: The 1966-1970 period was characterized by the absence of treatment and management policy. The 55 patients entered in this period experienced 70 and 56% survival at 5 and 10 yr, respectively, from diagnosis. The 1971-1974 period was characterized by the increasing knowledge of staging relevance and therapeutic approaches. The 153 patients who were treated in this period experienced 72 and 60% survival at 5 and 10 yr, respectively. The 1975-1980 period was characterized by a large combination of MOPP and radiotherapy. The 216 patients who entered this period observed 80 and 72.5% survival at 5 and 10 yr, respectively. The last therapeutic period (1980 to present time) is characterized by the increasing relevance of prognostic factors and alternating use of MOPP and ABVD as non-cross resistant regimen. The 83 patients who entered this period showed 90% survival at 5 yr. Both survival and disease-free survival were positively influenced by the change of therapeutic strategies during the four periods (P less than 0.005). Although better results have been recorded moving from one to the next therapeutic period, the present policy has been also based on the recognition of a high number of late complications due to the therapy. Preliminary results about the present therapeutic experience seem to indicate both a good remission rate and low incidence of complications.

Relapse rates of 75 patients with previously untreated Hodgkin's disease with stages I and II nodular sclerosis were analyzed according to the mediastinal involvement. The overall relapse rate was 22.6%. The probability of relapse was much greater for patients with large mediastinal involvement (66.6%) compared with 17% for patients with small mass, and 11.7% of patients without mediastinal involvement (P less than 0.001). There was no significant difference in recurrence rates between patients without mediastinal mass and patients with a small mass, and in these patients adjuvant chemotherapy MOPP after radiotherapy showed an evident benefit in reducing the relapse rate. On the other hand, no beneficial effect of adjuvant chemotherapy was observed in patients with large mediastinal involvement. Finally, in the 17 relapsing patients, 'salvage' chemotherapy was less effective in patients with large mediastinal mass than in those with small or no mediastinal involvement.

Splenectomized and asplenic persons are at risk of developing sudden episodes of meningitis and/or septicaemia, frequently due to Streptococcus pneumoniae (overwhelming postsplenectomy infection, or OPSI). The application of staging splenectomy to patients with Hodgkin's disease (HD) generated a new population at risk for OPSI. We reviewed the cases of sudden meningitis and/or septicaemia in a series of 491 consecutive adults with HD. No case was recorded among 149 non-splenectomized patients. 6 episodes of OPSI were observed in 5 of 342 splenectomized patients (crude frequency 1.75%, actuarial frequency at 10 yr 3.87%). The infecting organisms were Streptococcus pneumoniae (5 cases) and Salmonella enteritidis (1 case). 2 episodes (1 fatal) occurred during first complete remission (CR), 15 and 120 months, respectively, after splenectomy, 4 episodes (2 fatal) occurred after first relapse. For splenectomized patients in continuous CR, the cumulative risk of OPSI was 2.30% (95% CL 0-6.10%), and it was 15.25% (95% CL 0-35.37%) for splenectomized patients who had relapsed. These data suggest that, in adults with HD, the risk of OPSI should not limit the indication to staging splenectomy and does not warrant systematic prophylaxis. However, in splenectomized relapsed patients, OPSI can be a troublesome complication and appropriate prophylaxis could be useful.

Ninety-six patients with pathological stage IIIs Hodgkin's disease, uniformly treated with six cycles of MOPP and TNI, were retrospectively analysed in an effort to determine whether the lymphographic aspect of lymph nodes influence the prognosis. Case material was grouped according to the presence of lymph nodes less than 3 cm in diameter or larger at lymphography. Five-year survival and disease-free survival were 85 and 78% for patients with small lymph node involvement, compared to 48 and 30% for patients with larger lymph nodes. The comparative analysis between the lymphographic aspect and other prognostic factors shows that large lymphographic involvement is strongly correlated with the presence of large spleen involvement (P less than 0.0000029), followed by stage III2 (P less than 0.000612), followed by greater than or equal to 5 involved sites (P less than 0.012), followed by age greater than 40 yr (P less than 0.047). Conversely, no significant correlation was found with symptoms, histology and mediastinal involvement. Modifications of current treatment for both large and small lymph node involvement are discussed.

To obtain information relevant to the question of bone marrow transplantation, we examined the prognostic significance of disease features recorded at the time of diagnosis among 625 patients, aged 5 to 45, with Philadelphia chromosome-positive, nonblastic chronic granulocytic leukemia. The actuarial death rate for this population was 5% during the first year after diagnosis, 12% during the second year, and averaged 22.5% per year during the next eight years. Multivariable regression analysis of features recorded in nearly all cases indicated that sex, spleen size, hematocrit, platelet count, and percentage of circulating blasts were significant prognostic indicators. Analyses of additional data available in 113 to 421 cases suggested that serum lactic dehydrogenase activity, percentage of blasts in marrow, nucleated RBCs in blood, and percentage of basophils plus eosinophils might also provide useful prognostic information. A Cox model, generated with five variables representing features recorded regularly (the first five listed), permitted segregation of these patients into three groups with significantly different survival patterns. The high- risk group exhibited an actuarial mortality of 30% during the first two years after diagnosis and an annual risk of 30% thereafter. In contrast, the most favorable group had a two-year actuarial mortality of 9% and an average risk thereafter of 17% per year, with a median survival of 5 1/2 years. We conclude that it should be possible to classify potential candidates for bone marrow transplantation according to risk with conventional therapy. Such information may be useful in making decisions regarding early v deferred marrow transplantation.

Acute promyelocytic leukemia (APL) was diagnosed in 13 of 84 adult patients (15.4%) with acute myeloid leukemia (AML) first admitted between 1972 and 1976. All patients had clinical and/or laboratory evidence of defibrination syndrome. Four patients died of cerebral hemorrhage within 2 days of admission. Two patients died of generalized infection on days 7, and 16, respectively, after admission. The remaining 7 patients (54%) underwent complete remission (CR) with daunomycin, arabinosyl cytosine, and adriamycin. All patients received massive platelet transfusion, no heparin, and no granulocyte transfusion. CR was more frequent in patients with a very low blast cell count and a fibrinogen level higher than 100 mg/100 ml. Median survival of these seven CR patients with APL is similar (15 months) to that of CR patients with other types of AML treated at the same institution during the same period.

23 pts with lymphomas underwent intensive therapy and ABMT as hematological rescue (Table 1). NHL received BAVC1 regimen (16 pts) or CTX and TBI (pt. N. 13), followed by the reinfusion of the previously cryopreserved marrow. HL were treated with CTX, 3500 mg/m2, BCNU, 500 mg/m2, and VBL, 15 mg/m2, administered over a 4 hour period and received 24 hours later the autologous marrow stored at + 4 °C for 36 hours (6 pts). The clinical course after ABMT was uneventful in all but pt N. 17, and complete hematological recostitution was promptly achieved in all cases. The therapeutic response and current status of the pts are summarized in the Table. Complete remission occurred in 11 pts with NHL and in 8 cases further consolidation with radio and/or chemotherapy was administered. The experience in NHL suggests that untreated patients can tolerate well a high-dose regimen and that marrow cells harvested before chemotherapy permit a fast hematological recovery. BAVC regimen is sufficient to induce complete remissions: these pts should then receive, we feel, consolidation chemotherapy/ radiotherapy. However, in pts with lymphoblastic/immunoblastic histology or with very extensive disease the BAVC/ABMT regimen should not be used as the initial treatment.

85 patients with previously untreated Hodgkin's disease with stage I, II A and B nodular sclerosis were treated. 31 of them with stage I and II A were submitted to radiotherapy alone. All are alive, but 9 of them (30%) relapsed. On the contrary, 35 patients with stage I and II A, and 19 with stage I, II and IIE B were submitted to radiotherapy followed by three courses of MOPP. All 54 patients are alive and relapse-free. No severe complication related to chemotherapy was observed. The analysis of results suggests that 3 courses of MOPP can significantly (Ip0.00025) reduce the relapse rate in patients with stage I and II nodular sclerosis, eligible for radiotherapy, without increasing morbidity.

Abstract 3836 Background. In essential thrombocythemia (ET) patients history of thrombosis and age over 60 y are validated risk factors for thrombosis; the thrombocytosis is a constitutive abnormality associated with both thrombotic and hemorrhagic risk; JAK2 V617F mutation, leukocytosis, and male gender are candidate thrombotic risk factors. Aims. To evaluate in ET patients clinical-biological characteristics at diagnosis and their relationship with thrombosis occurrence before and after diagnosis. Methods. A cohort of ET patients of the Registro Italiano Trombocitemia (RIT) was retrospectively analysed. This preliminary report in detail considers data on thrombosis history. Results. A total of 977 patients, 387 males and 590 females, presented at diagnosis: median age 55 y, median PLT count 783 × 109/L, median WBC count 8.8 × 109/L, median Hb 14.1 g/dL, bone marrow fibrosis (grade >0) in 33% of cases, history of thrombosis in 189 cases (19.3%). The patients at high risk (age over 60 y and/or history of thrombosis) were 511 (52 %). The thrombosis history in univariate analysis was significantly related to: age over 60 y (p 0.001), male gender (p 0.045), low thrombocytosis (PLT 8.8 x109/L, p 0.01), and JAK2 V617F mutation (p 0.006). No relationship was found with the bone marrow fibrosis. The 977 patients, when both PLT count and WBC count at diagnosis were considered, were subdivided in four groups: group 1: 202 pts with low thrombocytosis and leukocytosis; group 2: 270 pts with low thrombocytosis and no leukocytosis; group 3: 272 pts with high thrombocytosis and leukocytosis; group 4: 197 pts with high thrombocytosis and no leukocytosis. In those patients, the thrombosis history was: 26.7% in the group 1(both risk factors); 24.1% in the group 2 (PLT risk factor); 20.2% in the group 3 (WBC risk factor); 7.6% in the group 4 (no risk factors). The rate of thrombosis history in patients with one or two of these risk factors was significantly (p 0.001) higher than in patients with no risk factors. The thrombotic events during the follow up (4088 pt-y) are still object of analysis. Conclusion. In this cohort of ET patients the rate of thrombosis history in univariate analysis was related to age over 60 y. Moreover, a significant relationship was found with PLT count at diagnosis below the median value (783 x109/L), WBC count at diagnosis over the median value (8.8 x109/L), JAK2 V617F mutation, and male gender. Disclosures: No relevant conflicts of interest to declare.

Abstract 3562 Aim of the present study was to evaluate the clinical outcome of a large series of younger patients with symptomatic multiple myeloma (MM) who were enrolled in two subsequent clinical trials of thalidomide-dexamethasone (thal-dex) incorporated into double autologous stem-cell transplantation (ASCT) to support high-dose melphalan (200 mg/m2). In both studies, thal (100 mg/day for the first 14 days and then 200 mg/day) and pulsed dex (between 480 and 160 mg per cycle), were administered from the onset until the second ASCT. The analysis was performed on an intention-to-treat basis on a total of 593 patients who were followed for a median of 36 months. The best VGPR and CR rates were 69% and 35%, respectively. The median duration of CR was 66 months. Median TTP and PFS were 53 and 44 months, respectively. The 5-year projected rates of TTP and PFS were 46% and 38%, respectively, while the corresponding value for OS was 67%. More than 80% of the patients were screened at diagnosis for the presence of cytogenetic abnormalities by FISH analysis. Forty-five percent of patients had del(13q), while t(4;14) and del(17p) were found in 16 % and 7 % of patients, respectively. The presence of del(17p) and/or t(4;14) was associated with a significantly shorter 5-year projected TTP, PFS and OS in comparison with the absence of these abnormalities, indifferently from the presence or absence of del(13q) (TTP: 30% vs 53%, respectively P=0.0000; PFS: 28% vs 45%, respectively, P=0.0000; OS: 53% vs 69%, respectively, P=0.0000). OS and PFS curves of patients carrying del(13q) alone were almost superimposable to those of patients without cytogenetic abnormalities, while TTP was significantly shorter for patients with del(13q) alone (5-year projected rates: 40% vs 53%, respectively, P=0.04). Patients carrying del(17p) in the absence of t(4;14) had similar 5-year projected TTP and PFS as compared with t(4;14) positive but del(17p) negative patients. However, OS was significantly shorter for the subgroup with del(17p) and absence of t(4;14) in comparison with that of patients carrying t(4;14) without del(17p) (5 year projected rates: 18% vs 70%, respectively, P=0.03). In a multivariate analysis, presence of del(17p) and high beta2-m at baseline were the most important variables adversely influencing TTP (HR: 2.3, P=0.001 and HR: 1.8, P=0.002, respectively), PFS (HR: 2.0, P=0.001 and HR: 1.9, P=0.001, respectively), and OS (HR: 3.9, P=0.000 and HR: 2.0, P=0.005, respectively). Additional variables predicting for shorter TTP and PFS were the presence of t(4;14) (HR: 1.8, P=0.004) and of del(13q) (HR: 1.6, P= 0.009). Also the quality of best response to the overall treatment program influenced clinical outcomes. In particular, patients achieving CR had a significantly longer PFS and OS than those achieving a VGPR (PFS: median 68 vs 40 months, respectively, P=0.007; 5-year projected OS rates: 84% vs 70%, respectively, P=0.01). In conclusion, incorporation of thal-dex into double autotransplantation failed to overcome the poor prognosis conferred by del(13 q), t(4;14) and del(17p). In a multivariate Cox regression analysis, del(17p) and high levels of serum beta2-m at diagnosis were the strongest variables adversely influencing PFS and OS. In comparison with the presence of t(4;14) but absence of del(17p), patients carrying del(17p) without t(4;14) had a significantly shorter OS, possibly due to their worst outcome after relapse. Presence of del(13q) alone conferred a significantly shorter TTP, but did not have an adverse impact on OS due to the favorable role of effective salvage therapies incorporating either bortezomib or lenalidomide. Disclosures: Off Label Use: use of first line thalidomide in preparation for ASCT. Cavo:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, no; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, no.