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Locatelli: Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Parasole:Baxalta: Membership on an entity's Board of Directors or advisory committees; behring: Consultancy; jazz: Honoraria, Speakers Bureau.

Molica: Gilead: Other: Advisory board; AbbVie: Other: Advisory board; Roche: Other: Advisory board; Jansen: Other: Advisory board. Levato:Novartis: Other: Advisory board. Shanafelt:Genentech: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding; Pharmacyclics: Research Funding.

BackgroundCurrently, only genetic testing, del(17p) or TP53, determines choices of therapy in chronic lymphocytic leukemia (CLL) whereas mutational status of IGHVand 11q deletion are not recognized as reliable parameters for treatment selection (with exception for fludarabine, cyclophosphamide and rituximab [FCR] in mutated IGHV).

Recently, a novel subgroup of B Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL), called Philadelphia-like(Ph-like) ALL, has been described. This high-risk group, despite the absence of BCR-ABL1rearrangement, shows genomic abnormalities that result in aberrant expression of cytokine receptors genes or tyrosine-kinase-activating signaling. These patients are poor responder to conventional chemotherapy but potentially sensitive to Tyrosine-Kinase Inhibitors (TKIs).

Background: The chronic lymphocytic leukemia international prognostic index (CLL-IPI) was first reported in 2015 and published in 2016 (Lancet Oncology 17:779). The utility of this prognostic tool has been confirmed in independent validation studies across countries and in different practice settings (i.e., clinical trials, academic medical centers, national population based cohorts). However, there are subtle differences of median survival of each risk category across series and limited information is available on the utility of the tool to predict time from diagnosis to first treatment (TTFT). To increase understanding of these important clinical questions, we conducted a systematic review and meta-analysis which includes all published studies that have used CLL-IPI to predict clinical outcome of CLL.

Molica: Gilead Sciences: Speakers Bureau; Roche Italy: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees.

Clinical outcome of patients with chronic lymphocytic leukemia (CLL) is often poor due to the high prevalence of comorbidities as well as functional impairment that characterize this population. However, a consensus on the definition and measurement of frailty is lacking.

No relevant conflicts of interest to declare.

The CLL-IPI score is a large cooperative effort in which clinical data collected from 8 randomized trials were used to develop an internationally applicable prognostic index for CLL patients. The model includes 5 independent parameters that predict for overall survival such as age, clinical stage, del(17p) and/or TP53 mutation, IGHV mutation status and β2-microglobulin (B2M) level. A potential limitation for an extensive use of CLL-IPI is represented, however, by the fact that only 20% of patients included in the full analysis set had early disease.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 4601

Foá: Genzyme: Membership on an entity's Board of Directors or advisory committees.

Abstract 2471

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of CD26 (dipeptidyl peptidase IV, DPP IV) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-CLL patients. By using a commercial ELISA (Human DPPIV/CD26 QuantikineR D Systems, USA) we found that circulating levels of CD26 did not reflect Rai sub-stages (P=0.52), β2-microglobulin (P=0.68), LDH (P=0.06), mutational status of IgVH(P=0.28), ZAP-70 (P=0.52) and CD38 (P=0.48). We used an optimal cut-point search to determine how to best split soluble CD26 data. Maximally selected logrank statistics plots identified a CD26 serum concentration of 371 ng/mL as the best cut-off. Accordingly, patients who had CD26 levels higher than 371 ng/mL experienced a shorter TFT (median 40 months) in comparison to patients whose CD26 levels were lower than 371 ng/mL (median 120 months; P=0.003). The univariate Cox proportional hazard model identified higher serum concentration of CD26 and absence of mutation in IgVHas predictor of shorter TFT. Again in multivariate analysis all these parameters maintained their discriminating power: mutational status of IgVH(HR= 0.23; CI 95% 0.10−0.51, P<0.0001), soluble CD26 (HR= 0.38; CI 95% 0.17−0.85, P=0.02). The effects of CD26 on TFT were masked by mutational status of IgVHin patients with unmutated IgVH. In contrast, serum levels of CD26 and mutational status of IgVHhad a joint effect on TFT in patients with mutated IgVHwhich translates into a segregation of patients with mutated IgVHin two sub-groups with different TFT according to CD26 levels (HR= 0.18; CI 95% 0.05−0.60, P=0.005). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble CD26 may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, CD26 along with mutational status of IgVHcan be adequately used to predict clinical behaviour of patients with low biological risk.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70− and CD38− expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 125 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently females (P=0.01), patients with Rai stage 0 (P=0.03), mutated IgVHdisease (P=0.008) and low ZAP-70 expression (P=0.04). In contrast, age (P=0.35), peripheral blood lymphocytosis (PBL)(P=0.09), hemoglobin (Hb) level (P=0.64), platelet (PLT) count (P=0.12), serum β2-m (P=0.49), LDH (P=0.85) and percentage of CD38-positive B-CLL cells (P=0.63) did not reflect circulating levels of BAFF. We used an optimal cut-point search to determine how to best split soluble BAFF data. Maximally selected log-rank statistics plots identified a BAFF serum concentration of 311 ng/mL as the best cut-off (P<0.0001). Accordingly, patients who had BAFF levels higher than 311 ng/mL experienced a longer TFT (median 108 months) in comparison to patients whose BAFF levels were lower than 311 ng/mL (median 30 months; P<0.0001). Along with serum concentration of BAFF, the univariate Cox proportional hazard model identified Rai substage I–II (P=0.003), lower PLT count (P=0.04), higher PBL count (P=0.01), increased LDH (P=0.01), ZAP-70 expression > 20% (P=0.02) and absence of mutation of IgVH(P<0.0001) as predictor of shorter TFT. In multivariate analysis only soluble BAFF (Hazard ratio [HR], 6.13; CI 95%, 2.31–16.25) and mutational status of IgVH,(HR= 2.99; CI 95% 1.33–6.76, P=0.008) maintained their discriminating power. The effects of BAFF on TFT were masked by mutational status of IgVHin patients with unmutated IgVH. However, serum levels of BAFF and mutational status of IgVHhad a joint effect on TFT in patients with mutated IgVHwhich translates into a segregation of patients with mutated IgVHin two groups with different TFT according to BAFF levels (HR= 8.9; P<0.0001). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, BAFF along with mutational status of IgVHcan be adequately used to predict clinical behaviour of patients with low biological risk.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of CD26 (dipeptidyl peptidase IV, DPP IV) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-CLL patients. By using a commercial ELISA (Human DPPIV/CD26 Quantikine R D Systems, USA) we found that circulating levels of CD26 did not reflect Rai sub-stages (P=0.52), β2-microglobulin (P=0.68), LDH (P=0.06), mutational status of IgVH (P=0.28), ZAP-70 (P=0.52) and CD38 (P=0.48). We used an optimal cut-point search to determine how to best split soluble CD26 data. Maximally selected logrank statistics plots identified a CD26 serum concentration of 371 ng/mL as the best cut-off. Accordingly, patients who had CD26 levels higher than 371 ng/mL experienced a shorter TFT (median 40 months) in comparison to patients whose CD26 levels were lower than 371 ng/mL (median 120 months; P=0.003). The univariate Cox proportional hazard model identified higher serum concentration of CD26 and absence of mutation in IgVH as predictor of shorter TFT. Again in multivariate analysis all these parameters maintained their discriminating power: mutational status of IgVH (HR= 0.23; CI 95% 0.10−0.51, P<0.0001), soluble CD26 (HR= 0.38; CI 95% 0.17−0.85, P=0.02). The effects of CD26 on TFT were masked by mutational status of IgVH in patients with unmutated IgVH. In contrast, serum levels of CD26 and mutational status of IgVH had a joint effect on TFT in patients with mutated IgVH which translates into a segregation of patients with mutated IgVH in two sub-groups with different TFT according to CD26 levels (HR= 0.18; CI 95% 0.05−0.60, P=0.005). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble CD26 may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, CD26 along with mutational status of IgVH can be adequately used to predict clinical behaviour of patients with low biological risk.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70− and CD38− expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 125 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently females (P=0.01), patients with Rai stage 0 (P=0.03), mutated IgVH disease (P=0.008) and low ZAP-70 expression (P=0.04). In contrast, age (P=0.35), peripheral blood lymphocytosis (PBL)(P=0.09), hemoglobin (Hb) level (P=0.64), platelet (PLT) count (P=0.12), serum β2-m (P=0.49), LDH (P=0.85) and percentage of CD38-positive B-CLL cells (P=0.63) did not reflect circulating levels of BAFF. We used an optimal cut-point search to determine how to best split soluble BAFF data. Maximally selected log-rank statistics plots identified a BAFF serum concentration of 311 ng/mL as the best cut-off (P<0.0001). Accordingly, patients who had BAFF levels higher than 311 ng/mL experienced a longer TFT (median 108 months) in comparison to patients whose BAFF levels were lower than 311 ng/mL (median 30 months; P<0.0001). Along with serum concentration of BAFF, the univariate Cox proportional hazard model identified Rai substage I–II (P=0.003), lower PLT count (P=0.04), higher PBL count (P=0.01), increased LDH (P=0.01), ZAP-70 expression > 20% (P=0.02) and absence of mutation of IgVH (P<0.0001) as predictor of shorter TFT. In multivariate analysis only soluble BAFF (Hazard ratio [HR], 6.13; CI 95%, 2.31–16.25) and mutational status of IgVH, (HR= 2.99; CI 95% 1.33–6.76, P=0.008) maintained their discriminating power. The effects of BAFF on TFT were masked by mutational status of IgVH in patients with unmutated IgVH. However, serum levels of BAFF and mutational status of IgVH had a joint effect on TFT in patients with mutated IgVH which translates into a segregation of patients with mutated IgVH in two groups with different TFT according to BAFF levels (HR= 8.9; P<0.0001). Our results indicate that in early B-cell CLL biological profile including among other parameters soluble BAFF may provide a useful insight into the complex interrelationship of prognostic variables. Furthermore, BAFF along with mutational status of IgVH can be adequately used to predict clinical behaviour of patients with low biological risk.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently patients with Rai stage 0 (P=0.008) and mutated IgVH (P=0.03). In contrast, peripheral blood lymphocytosis (P=0.06), serum β2-m (P=0.159), LDH (P=0.333) and percentage of ZAP-70-positive (P=0.242) or CD38-positive B-CLL cells (P=0.142) did not reflect circulating levels of BAFF. The relationship among various bio-pathological parameters, analyzed by the multiple correspondence analysis (MCA), showed two different clinico-biological profiles. The first, characterized by higher BAFF serum levels (i.e., > 336 ng/mL), presence of mutation in the IgVH, low percentage of CD38-positive B-CLL cells (< 30%) and low LDH was associated with a stable pattern of disease generally not requiring therapy. The second, defined by lower BAFF levels, absence of mutation in the IgVH, high percentage of CD38- positive B-CLL cells and high LDH was associated with a more progressive pattern of disease and a shorter TFT. After a median follow-up time of 35 months (range, 2–120 months) 26 (37.6%) out of 69 patients experienced a need for chemotherapy. Kaplan-Meier estimates of patientsTFT, plotted after searching the best cut-off for BAFF (i.e., 336 ng/mL), demonstrated that low BAFF concentration was associated with a shorter TFT (median TFT 36 months) while median was not reached by patients with BAFF levels higher than 336 ng/mL (P<0.0001). Along with lower serum levels of BAFF (Hazard Ratio [HR], 0.19; P<0.0001), the univariate Cox proportional hazard model identified absence of mutation in IgVH (HR, 0.17; P<0.0001), CD38-positivity (HR, 3.32; P=0.01) and lower platelet count (HR, 0.19; P=0.03) as predictor of shorter TFT. Finally, in multivariate analysis only mutational status of IgVH (HR, 0.25; P=0.007) and serum concentration of BAFF (HR, 034; P=0.04) affected significantly TFT. Our results indicate that in early B-cell CLL clinico-biological profile including among other parameters BAFF may provide a useful insight into the complex interrelationship of prognostic variables and semplify their interpretation. The possible presence of BAFF isoform in B-CLL could peraphs account for the unexpected correlation between low soluble BAFF levels and poor clinical outcome in patients with early disease.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of BAFF (B-cell activating factor of the TNF family) by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-cell CLL patients. By using a commercial ELISA (R & D Systems, USA) we found that higher levels of BAFF characterized more frequently patients with Rai stage 0 (P=0.008) and mutated IgVH(P=0.03). In contrast, peripheral blood lymphocytosis (P=0.06), serum β2-m (P=0.159), LDH (P=0.333) and percentage of ZAP-70-positive (P=0.242) or CD38-positive B-CLL cells (P=0.142) did not reflect circulating levels of BAFF. The relationship among various bio-pathological parameters, analyzed by the multiple correspondence analysis (MCA), showed two different clinico-biological profiles. The first, characterized by higher BAFF serum levels (i.e., > 336 ng/mL), presence of mutation in the IgVH, low percentage of CD38-positive B-CLL cells (< 30%) and low LDH was associated with a stable pattern of disease generally not requiring therapy. The second, defined by lower BAFF levels, absence of mutation in the IgVH, high percentage of CD38- positive B-CLL cells and high LDH was associated with a more progressive pattern of disease and a shorter TFT. After a median follow-up time of 35 months (range, 2–120 months) 26 (37.6%) out of 69 patients experienced a need for chemotherapy. Kaplan-Meier estimates of patientsTFT, plotted after searching the best cut-off for BAFF (i.e., 336 ng/mL), demonstrated that low BAFF concentration was associated with a shorter TFT (median TFT 36 months) while median was not reached by patients with BAFF levels higher than 336 ng/mL (P<0.0001). Along with lower serum levels of BAFF (Hazard Ratio [HR], 0.19; P<0.0001), the univariate Cox proportional hazard model identified absence of mutation in IgVH(HR, 0.17; P<0.0001), CD38-positivity (HR, 3.32; P=0.01) and lower platelet count (HR, 0.19; P=0.03) as predictor of shorter TFT. Finally, in multivariate analysis only mutational status of IgVH(HR, 0.25; P=0.007) and serum concentration of BAFF (HR, 034; P=0.04) affected significantly TFT. Our results indicate that in early B-cell CLL clinico-biological profile including among other parameters BAFF may provide a useful insight into the complex interrelationship of prognostic variables and semplify their interpretation. The possible presence of BAFF isoform in B-CLL could peraphs account for the unexpected correlation between low soluble BAFF levels and poor clinical outcome in patients with early disease.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of adiponectin by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-cell CLL patients. Higher levels of adiponectin inversely correlated with peripheral blood lymphocytosis (r=−0.254; P=0.03), male gender (P=0.0002), percentage of ZAP−70-positive (r=− 0.285; P=0.04) and CD38-positive (r=−0.294; P=0.04) B-CLL cells. After a median follow-up time of 32 months (range, 2–120 months) 28 (40.5%) out of 69 patients experienced a need for chemotherapy. Kaplan-Meier estimates of patients’ TFT, plotted after searching the best cut-off for adiponectin (i.e., 5.88 μg/mL ), demonstrated that low adiponectin concentration was associated with a shorter TFT (median TFT 32 months; P=0.01). The relationship among the various bio-pathological parameters, analyzed by the multiple correspondence analysis (MCA), showed two different clinico-biological profiles. The first, characterized by higher adiponectin serum levels (i.e., > 5.88 μg/mL), higher platelet count (> 174 x 109/L), lower β2-microglobulin [β2-m] (< 2.35 mg/L), presence of mutation in the IgVH and low percentage of either CD38-positive (< 20%) or ZAP-70-positive (< 20%) B-CLL cells, was associated with a stable pattern of disease generally not requiring therapy. The second, defined by lower adiponectin levels, lower platelet count, high β2-m concentration, absence of mutation in the IgVH, high percentage of CD38- and ZAP-70 positive B-cells, was associated with a more progressive pattern of disease and a shorter TFT. The univariate Cox proportional hazard model demonstrated that in addition with lower serum levels of adiponectin (Hazard Ratio [HR], 2.936; P=0.01), the absence of IgVH mutational status (HR, 6.378; P=0.002) and ZAP-70-positivity (HR, 3.314; P=0.02) were associated with a shorter TFT. However, in multivariate analysis only ZAP-70 positivity emerged as predictor of the TFT (HR, 5.187; P=0.008). Our results indicate that in early B-cell CLL clinico-biological profile including among other parameters adiponectin may provide a useful insight into the complex interrelationship of prognostic variables and semplify their interpretation. However, adiponectin may not replace the need for the determination of ZAP-70 and IgVH mutational status.

We evaluated microvessel area of bone marrow (BM) samples from 20 patients with advanced CLL (i.e., symptomatic Binet stage A, B or C) who received at least 8 weeks, after the end of treatment with fludarabine, subcutaneous alemtuzumab, three times weekly for 6 weeks, at escalating dose up to 10 mg. The patient sample included 14 males and 6 females with a median age of 51 years (range 44–60). After a median number of 6 cycles of fludarabine (range, 4–13), 11 (55%) patients could be classified in complete remission (CR) and 9 (45%) in partial remission (PR) (7 nodular-PR and 2 PR). Interestingly, the rate of CR increased to 90% (18 CR; P=0.03; Fisher's exact test) after treatment with alemtuzumab. In keeping with hematological responses, significant changes in BM microvessel area were observed The decrease of BM angiogenesis, observed virtually in all patients, was a continuous process characterizing the sequential use of fludarabine and alemtuzumab (P = 0.002; Kruskal-Wallis test). This conspicuous feature was easily demonstrable in either ZAP-70-positive (P = 0.02) or ZAP-70-negative (P = 0.001) patients.

We evaluated microvessel area of bone marrow (BM) samples from 20 patients with advanced CLL (i.e., symptomatic Binet stage A, B or C) who received at least 8 weeks, after the end of treatment with fludarabine, subcutaneous alemtuzumab, three times weekly for 6 weeks, at escalating dose up to 10 mg. The patient sample included 14 males and 6 females with a median age of 51 years (range 44–60). After a median number of 6 cycles of fludarabine (range, 4–13), 11 (55%) patients could be classified in complete remission (CR) and 9 (45%) in partial remission (PR) (7 nodular-PR and 2 PR). Interestingly, the rate of CR increased to 90% (18 CR; P=0.03; Fisher’s exact test) after treatment with alemtuzumab. In keeping with hematological responses, significant changes in BM microvessel area were observed The decrease of BM angiogenesis, observed virtually in all patients, was a continuous process characterizing the sequential use of fludarabine and alemtuzumab (P = 0.002; Kruskal-Wallis test). This conspicuous feature was easily demonstrable in either ZAP-70-positive (P = 0.02) or ZAP-70-negative (P = 0.001) patients. Residual disease was assessed using a consensus polymerase chain reaction (PCR) methodology to detect the clonality of IgH sequences. Thirteen out of 20 (65%) patients changed from a monoclonal to a polyclonal pattern of IgH after alemtuzumab consolidation. We wondered whether molecular response could translate into a change in the BM microvessel area. A separate evaluation carried out in patients with a persistent monoclonal pattern and in those who changed to a polyclonal pattern of IgH after alemtuzumab therapy showed a significant reduction of BM microvessel area only in the latter (P = 0.0002). A new information provided by the present study concerns the impact of the cumulative dose of alemtuzumab on either molecular response or reduction in BM angiogenesis. Analysis carried out after setting as cut-off the median cumulative dose of alemtuzumab (i.e., 184 mg; range, 134–187) revealed a dose-response relationship. Only two (15.3%) out of 13 patients who received a cumulative dose of alemtuzumab higher than 184 mg had persistent monoclonal IgH in comparison to 5 (71.4%) out 7 patients who had received a cumulative dose of alemtuzumab lower than median (P = 0.007). Similarly, a significant decrease in the extent of microvessel area was observed among patients whose cumulative dose was equal or higher than 184 mg (P = 0.0001) while the same did not apply for a cumulative dose of alemtuzumab lower than 184 mg (P = 0.09). Overall, these data demonstrate a decrease in BM vascularity after treatment with alemtuzumab, which reflects both molecular response and cumulative dose of this drug, and suggest a potential use of alemtuzumab as anti-angiogenic agent in the treatment of advanced CLL.

We analyzed the correlation between well-established biological parameters of prognostic relevance in B-cell chronic lymphocytic leukemia [CLL] (i.e, mutational status of the immunoglobulin heavy chain variable region [IgVH], ZAP-70- and CD38-expression) and serum levels of adiponectin by evaluating the impact of these variables on the time to first treatment [TFT] in a series of 69 previously untreated Binet stage A B-cell CLL patients. Higher levels of adiponectin inversely correlated with peripheral blood lymphocytosis (r=−0.254; P=0.03), male gender (P=0.0002), percentage of ZAP−70-positive (r=− 0.285; P=0.04) and CD38-positive (r=−0.294; P=0.04) B-CLL cells.

HCV-associated B-cell non-Hodgkin’s lymphomas (NHL) show distinctive clinico-pathological features such as older age, liver damage, presence of monoclonal gammopathy, increased incidence of autoimmune disorders, extranodal localizations and restricted histological subtypes. As far as B-cell chronic lymphocytic leukemia (CLL) is concerned, information dealing with either characteristics or outcome of HCV-associated CLL are limited. With this background we compared clinico-hematological features and outcome of 34 HCV-positive patients diagnosed at our institution as having immunologically typical B-cell CLL (i.e., CD5+/CD23+/CD79b-/SmIg dim) with 161 unselected CLL HCV-negative patients followed-up in the last 10 years. The two groups were alike with respect to main clinico-hematological features such as age (P=0.780), sex (P=0.650), absolute lymphocyte count (P=0.788), platelet count (P=0.362), haemoglobin level (P=0.704), β2-microglobulin (P=0.192), Binet stage distribution (P=0.224) and lymphocyte doubling time (LDT)(P= 0.620). As expected either ALT or AST serum levels at the time of CLL diagnosis were significantly higher in HCV-positive patients in comparison to HCV-negative ones (P<0.0001 for both). In contrast, no difference was found in the incidence of monoclonal gammopathy between HCV-positive and HCV-negative patients (10.3% versus 7.7%; P=0.708). The same applied for autoimmune disorders which were homogeneously distributed in the two subgroups (P=0.711) and accounted, more frequently, for autoimmune emolytic anemia (AEA)(HCV-negative subgroup, 5.5%; HCV-positive subgroup, 9.0%). The proportion of severe infections registered did not reflect the HCV-status (HCV-negative subgroup, 9.6%; HCV-positive subgroup 6.4%; P= 0.510). Also second tumours were equally distributed among HCV-positive and HCV-negative subgroups (10% versus 6.8%; P=0.655). Survival curves projected at 10 years did not show any statistical in terms overall survival (Hazard Risk, 0.690; 95% CI: 0.216–1.304; P=0.167). Finally, the short term hepatic toxicity of chemotherapy did not increase among HCV-positive patients (P=0.671). In conclusion, HCV-positive patients with B-cell CLL do not differ from other patients both for presentation and clinical outcome. The need to activate specific protocols of antiviral therapy appears less urgent in comparison to NHL, however, younger CLL patients HCV-positive who are eligible for therapies at higher immunosuppressive potential (i.e., chemo-immunotherapy) should be taken in special consideration.

HCV-associated B-cell non-Hodgkin's lymphomas (NHL) show distinctive clinico-pathological features such as older age, liver damage, presence of monoclonal gammopathy, increased incidence of autoimmune disorders, extranodal localizations and restricted histological subtypes. As far as B-cell chronic lymphocytic leukemia (CLL) is concerned, information dealing with either characteristics or outcome of HCV-associated CLL are limited. With this background we compared clinico-hematological features and outcome of 34 HCV-positive patients diagnosed at our institution as having immunologically typical B-cell CLL (i.e., CD5+/CD23+/CD79b-/SmIg dim) with 161 unselected CLL HCV-negative patients followed-up in the last 10 years. The two groups were alike with respect to main clinico-hematological features such as age (P=0.780), sex (P=0.650), absolute lymphocyte count (P=0.788), platelet count (P=0.362), haemoglobin level (P=0.704), β2-microglobulin (P=0.192), Binet stage distribution (P=0.224) and lymphocyte doubling time (LDT)(P= 0.620). As expected either ALT or AST serum levels at the time of CLL diagnosis were significantly higher in HCV-positive patients in comparison to HCV-negative ones (P<0.0001 for both). In contrast, no difference was found in the incidence of monoclonal gammopathy between HCV-positive and HCV-negative patients (10.3% versus 7.7%; P=0.708). The same applied for autoimmune disorders which were homogeneously distributed in the two subgroups (P=0.711) and accounted, more frequently, for autoimmune emolytic anemia (AEA)(HCV-negative subgroup, 5.5%; HCV-positive subgroup, 9.0%). The proportion of severe infections registered did not reflect the HCV-status (HCV-negative subgroup, 9.6%; HCV-positive subgroup 6.4%; P= 0.510). Also second tumours were equally distributed among HCV-positive and HCV-negative subgroups (10% versus 6.8%; P=0.655). Survival curves projected at 10 years did not show any statistical in terms overall survival (Hazard Risk, 0.690; 95% CI: 0.216–1.304; P=0.167). Finally, the short term hepatic toxicity of chemotherapy did not increase among HCV-positive patients (P=0.671).

Insulin like growth factor 1 (IGF-1) is an important growth and antiapoptotic factor for the cancer cells in several malignancies and in multiple myeloma recent studies support the hypotesis of a role for IGF-1 in disease progression. Clinico-biological relevance of IGF-1 was never studied in B-cell chronic lymphocytic leukemia (CLL). Using a quantitative sandwich immunoassay technique (ELISA)(QUANTIKINE®, Human IGF-1 and IGFBP-3, R & D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. Either IGF-1 or IGFBP-3 were significantly decreased compared to healthy age- and sex-matched controls (P<0.0001 for both; Mann-Whitney test). Serum levels of IGF-1 and IGFBP-3 paralleled each other (P=0.002); in contrast, no significant correlation was found between serum levels of IGF-1 and clinico-hematological variables including age (P=0.253), sex (P=0.270), Rai clinical substages (P=0.140), LDH (P=0.956), β2-microglobulin (P=0.368), lymphocyte count (P=0.703) and lymphocyte doubling time [LDT](P=0.233). When correlation were attempted with circulating levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF)(P=0.971), basic fibroblastic growth factor (FGF-2)(P=0.695), angiogenin (P=0.282) or adhesion molecules such as vascular cell adhesion molecule-1 [VCAM-1] (P=0.318), intercellular adhesion molecule-1 [ICAM-1] (P=0.883) and platelet endothelial cell adhesion-1 [PECAM-1] (P=0.772) similar results were found. Serum levels of IGF-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an endpoint surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with the cutoff point at the 75th percentile of IGF-1 levels (i.e., 93 pg/ml). Median PFS was 63 months in the patient group with low IGF-1, compared to a median PFS of 40 months in the remaining patients (P=0.002; HR, 0.311, 95% C.I, 0.085–0.630). In the multivariate analysis performed including variables significant at univariate analysis [i.e., Rai substage (P=0.002); LDT (P=0.004), IGF-1 (P=0.01)], only Rai substage retained prognostic significance (P=0.006). However, after removing from analysis LDT (only 6 out of 77 had an LDT< 12 months), either IGF-1 or Rai substage entered the model at a significant level ((P=0.03 and P=0.01, respectively). In conclusion, IGF-1 did not correlate with markers of tumor burden or clinical status in CLL thus suggesting that levels of this cytokine do not reflect the intrinsic malignancy of disease. Results of the present study highlight, however, its involvement in mechanisms of disease-progression in early CLL.

Insulin like growth factor 1 (IGF-1) is an important growth and antiapoptotic factor for the cancer cells in several malignancies and in multiple myeloma recent studies support the hypotesis of a role for IGF-1 in disease progression. Clinico-biological relevance of IGF-1 was never studied in B-cell chronic lymphocytic leukemia (CLL). Using a quantitative sandwich immunoassay technique (ELISA)(QUANTIKINE®, Human IGF-1 and IGFBP-3, R & D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. Either IGF-1 or IGFBP-3 were significantly decreased compared to healthy age- and sex-matched controls (P<0.0001 for both; Mann-Whitney test).