Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study.

To retrospectively assess the efficacy of bendamustine alone and with rituximab (R-B), 109 patients with relapsed chronic lymphocytic leukaemia (CLL) were enrolled in 24 Italian centres. The median age was 66 years (range 39-85). Forty-three percent of patients had relapsed and 57% were resistant (median previous therapies = 3; range 1-8). Twenty-two patients received bendamustine alone and 87 patients received R-B (median B dosage: 100 mg/m(2) per day, range 90-130 mg/m(2) per day). The overall response rate was 69·6% (complete response 28·6%; partial response 41%), and was significantly higher in patients treated with R-B (P = 0·014) and in those responsive to the previous treatment (P=0·04). After a median follow-up of 7·9 months (range 1-148), the median progression-free survival was 16 months and the median duration of response was 13 months. Median overall survival (OS) was 16·8 months for the whole cohort; patients not responding to the treatment had a significantly worse outcome than those who attained a response (P = 0·0001). In multivariate analysis, only resistant disease status at start of bendamustine treatment (HR 3·2, 95% CI 1·4-7·3, P = 0·006) had an independent prognostic value for OS. Toxicity was manageable and mostly haematological. In conclusion, in our experience R-B was an effective and well-tolerated treatment for relapsed/refractory CLL patients, producing a remarkable high CR rate and mild toxicity.

Single-dose palonosetron for prevention of chemotherapy-induced nausea and vomiting in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy containing steroids: results of a phase II study from the Gruppo Italiano per lo Studio dei Linfomi (GISL).

PURPOSE: The control of nausea and vomiting induced by chemotherapy is paramount for overall treatment success in cancer patients. Antiemetic therapy during chemotherapy in lymphoma patients generally consists of anti-serotoninergic drugs and dexamethasone. The aim of this trial was to evaluate the efficacy of a single dose of palonosetron, a second-generation serotonin type 3 (5-HT(3)) receptor antagonist, in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy (MEC) containing steroids. METHODS: Patients received a single intravenous bolus of palonosetron (0.25 mg) before administration of chemotherapy. Complete response (CR) defined as no vomiting and no rescue therapy during overall phase (0-120 h) was the primary endpoint. Complete control (CC) defined as CR and only mild nausea was a secondary endpoint. RESULTS: Eighty-six evaluable patients entered in the study. A CR was observed in 74 patients (86.0%) during the overall phase; the CR during the acute (0-24 h) and delayed (24-120 h) phases was 90.7% and 88.4%, respectively. CC was 89.5% during the acute and 84.9% during the delayed phase; the overall CC was 82.6%. CONCLUSIONS: This was the first trial, which demonstrated the efficacy of a single dose of palonosetron in control CINV in patients with aggressive non-Hodgkin's lymphoma receiving MEC regimen containing steroids.

Vinorelbine, gemcitabine, procarbazine and prednisone (ViGePP) as salvage therapy in relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL): results of a phase II study conducted by the Gruppo Italiano per lo Studio dei Linfomi.

Patients with aggressive NHL who fail initial treatment or subsequently relapse have a very poor outcome and less than 20-25% achieve a prolonged disease-free interval with salvage therapies. To improve the outcome of patients with refractory aggressive NHL not suitable for High Dose Therapy (HDT) and Autologous Stem Cell Transplant (ASCT), the efficacy of a combination of gemcitabine, vinorelbine, procarbazine and prednisone (ViGePP) were tested. Between November 1999 and September 2002, 69 patients with relapsed or refractory aggressive NHL were treated with ViGePP regimen, every 4 weeks up to six courses. At the end of planned chemotherapy patients could receive additional radiotherapy on residual masses or on sites of previously bulky disease. Sixty-six patients were available for evaluation of study end-points. Thirty patients were refractory to therapy and 36 patients had relapsed after remission obtained with previous therapy. At the end of therapy, complete remission (CR) rate was 23%, 3-year relapse free survival rate was 40% and 3-year overall survival rate was 25% for the whole series (29% and 20% for relapsed and refractory patients, respectively). Patients achieving CR with ViGePP had a significantly better survival as compared with the remaining ones (p = 0.0003). ViGePP as used in the present setting has demonstrated a promising activity, comparable to other conventional dose regimens. Although CR was achieved only in a minority of patients, this was durable in a significant proportion of them. This regimen should be tested in less heavily pre-treated patients and probably in combination with new active agents such Rituximab. Further developments of this combination are warranted.

Role of glutathione-S-transferase (GST) polymorphisms in patients with advanced Hodgkin lymphoma: results from the HD2000 GISL trial.

Polymorphisms of the Glutathione-S Transferase (GST) family may influence the prognosis in lymphoma patients. We aimed to validate the impact of GSTT1 and GSTM1 deletions and of the GSTP1Ile105Val polymorphism on outcome and toxicity in 140 patients with advanced Hodgkin's lymphoma enrolled in the prospective multicenter HD2000-GISL trial, comparing ABVD, BEACOPP and CEC regimens. Carriers of the GSTP1Ile105Val polymorphism had a higher rate of grade 3-4 anemia following treatment. Overall, our study failed to validate GST genotyping as prognostic factor for progression-free survival (PFS). Only the small cohort of patients with an international prognostic score (IPS) >3 and undeleted GSTT1 and/or GSTM1, treated with ABVD had worse progression-free survival (PFS) (GSTT1 + vs GSTT1-: HR 5.02, 95% C.I., 1.16-21.8, p = 0.031, GSTM1 + /GSTT1 + vs GSTM1-and/or GSTT1-: HR 4.61, 95% C.I. 1.28- 16.6, p = 0.019, respectively). No differences were observed for patients treated with intensified regimens, as BEACOPP and CEC. In conclusion, the prognostic role of GST polymorphism, if at all, is limited to a small subgroup of patients treated with standard ABVD regimen.

Anthracyclines: a cornerstone in the management of non-Hodgkin's lymphoma.

Since anthracyclines were introduced in the treatment of non-Hodgkin's lymphoma in the late 1960s, they have been acknowledged as a cornerstone in the management of the disease and, in particular, of aggressive lymphomas. The high efficacy of anthracycline-containing regimens must, however, be balanced against the drug-related toxicity, which mainly affects the cardiovascular system and represents a major concern for clinicians, especially in the treatment of elderly patients. Patients' outcomes could be further improved, particularly for those at high risk of cardiotoxicity, by substituting liposomal doxorubicin for conventional doxorubicin. This approach has already been tested and shown to be effective in several cancers, especially in different subsets of patients with diffuse large B-cell lymphoma. The use of liposomal doxorubicin in combination regimens for other conditions, such as follicular lymphoma and splenic marginal zone lymphoma, is also under investigation, and early results are promising.

Long-term follow-up analysis of HD9601 trial comparing ABVD versus Stanford V versus MOPP/EBV/CAD in patients with newly diagnosed advanced-stage Hodgkin's lymphoma: a study from the Intergruppo Italiano Linfomi.

PURPOSE: The Intergruppo Italiano Linfomi HD9601 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus doxorubicin, vinblastine, mechloretamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V [StV]) versus the combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [MEC]) for the initial treatment of advanced-stage Hodgkin's lymphoma to select which regimen would best support a reduced radiotherapy program (limited to two or fewer sites of either previous bulky or partially remitting disease). Superiority of ABVD and MEC to StV was demonstrated. We report analysis of long-term outcome and toxicity. PATIENTS AND METHODS: Patients with stage IIB, III, or IV were randomly assigned among six cycles of ABVD, three cycles of StV, and six cycles of MEC; radiotherapy was administered in 76, 71, and 50 patients in the three arms, respectively. RESULTS: Currently, the median follow-up is 86 months; in the prolonged observation period, eight additional failures, including two relapses, both in the StV arm, and six additional deaths in complete response were recorded. The 10-year overall survival rates were 87%, 80%, and 78% for ABVD, MEC, and StV, respectively (P = .4). The 10-year failure-free survival was 75%, 74%, and 49% in the ABVD, MEC, and StV arms, respectively (P < .001). The 10-year disease-free survival of patients treated or not with radiotherapy (RT) showed no difference for ABVD or MEC (85% v 80% and 93% v 68%), and a statistically significant difference for StV (76% v 33%; P = .004). No significant long-term toxicity was recorded. CONCLUSION: The long-term analysis confirmed ABVD and MEC superiority to StV. The use of RT after StV was established as mandatory. ABVD is still to be considered as the standard treatment with a good balance between efficacy and toxicity.

Prognostic tools in follicular lymphomas.

Despite significant improvements in treatment modalities over the 10 years, the clinical course of patients with follicular lymphoma (FL) remains heterogeneous. Thus, prognostic indexes are still required to direct treatment choices and for the design of clinical trials. Investigators have conducted a variety of studies aimed at integrated assessment of biological and clinical features in order to identify novel prognostic factors and scoring systems. Genetic studies focused on tumor cells and the tumor microenvironment represent a step forward in understanding the biology of FL and are likely to provide new prognostic tools for future clinical use. Several prognostic factors have been identified and are currently used in combination to establish prognostic scores and to support therapeutic decisions. The FL International Prognostic Index (FLIPI) is currently used for defining individual risk of death. More recently, FLIPI2 was developed by the same group that built FLIPI as a new model for prognostic definition of patients with FL. The model was defined using prospectively collected data from patients who also received the monoclonal therapeutic antibody rituximab and stratifies patients into three risk categories for disease progression. Since many biological factors are not yet clinically validated or easily assessable, clinical data still represent the major source of prognostic information. The progressive development of new and more effective therapies for the treatment of FL makes the study of prognosis a dynamic and evolving area of clinical research.

ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial.

PURPOSE: To compare doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (COPPEBVCAD; CEC) for advanced Hodgkin's lymphoma (HL). PATIENTS AND METHODS: Three hundred seven patients with advanced HL (stage IIB, III, and IV) were randomly assigned to receive six courses of ABVD, four escalated plus two standard courses of BEACOPP, or six courses of CEC, plus a limited radiation therapy program. RESULTS: After a median follow-up of 41 months, BEACOPP resulted in a superior progression-free survival (PFS), with a significant reduction in risk of progression (hazard ratio [HR] = 0.50) compared with ABVD. No differences between BEACOPP and CEC, or CEC and ABVD were observed. The 5-year PFS was 68% (95% CI, 56% to 78%), 81% (95% CI, 70% to 89%), and 78% (95% CI, 68% to 86%), for ABVD, BEACOPP, and CEC, respectively (BEACOPP v ABVD, P = .038; CEC v ABVD and BEACOPP v CEC, P = not significant [NS]). The 5-year overall survival was 84% (95% CI, 69% to 92%), 92% (95% CI, 84% to 96%), and 91% (95% CI, 81% to 96%) for ABVD, BEACOPP, and CEC, respectively (P = NS). BEACOPP and CEC resulted in higher rates of grade 3-4 neutropenia than ABVD (P = .016); BEACOPP was associated with higher rates of severe infections than ABVD and CEC (P = .003). CONCLUSION: As adopted in this study BEACOPP is associated with a significantly improved PFS compared with ABVD, with a predictable higher acute toxicity.

Incidence, clinical characteristics and survival of malignant lymphomas: a population-based study from a cancer registry in northern Italy.

We conducted a population-based study of peripheral lymphomas (PL) that had been diagnosed between 1997 and 2003 in the province of Modena, Italy, with the aim of providing updated incidence, clinical and survival data for these cancers. We evaluated the incidence patterns and time trends of 1582 cases of PL that had been reclassified according to the WHO classification of hematological malignancies. Data regarding clinical characteristics, treatment and outcome were also collected for each case. The World Age-Standardized Rate (ASR) was calculated as 13.4, 2.2 and 3.4 per 100,000 people for B-cell non-Hodgkin's lymphoma (NHL), T-cell NHL and Hodgkin's Lymphoma (HL), respectively, with an increase of 1.62% per year during the study period. The lymphoma subtype showing the highest incidence was found to be diffuse large B-cell lymphoma (DLBCL) with an ASR of 4.8. Compared with reports from other western countries, our series is characterized by a higher incidence of HL and indolent B-NHL in general, and of CLL/SLL (ASR = 3.3) and marginal zone NHL (ASR = 1.5), in particular, and also by a lower incidence of FL (ASR = 2). After a median follow-up of 54 months, the 5-year relative survival for the whole series was found to be 70% with a statistically significant improvement for cases diagnosed during 2002-2003 (from 66 to 74%; p = 0.03). Survival improvement within the study period was also evident for patients with DLBCL, HL and T-NHL. Our study provides a comprehensive description of both the epidemiological and clinical features of PL cases in Modena and our data also reflect the major advances in the curability of some histological subtypes of this disease. The usefulness of a population-based approach to better characterizing different lymphoma subtypes is also demonstrated.

The length of treatment of aggressive non-Hodgkin's lymphomas established according to the international prognostic index score: long-term results of the GISL LA03 study.

OBJECTIVES: To compare two different schedules of two different anthracycline-containing regimens, where length of treatment is modulated according to the international prognostic index (IPI) in patients with aggressive non-Hodgkin's Lymphoma (NHL). METHODS: In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2 x 2 factorial phase III clinical trial for patients with newly diagnosed aggressive NHL comparing ProME(Epidoxorubicin)CE-CytaBOM (PE-C) to ProMI(Idarubicin)CE-CytaBOM (PI-C) and a fixed to a flexible treatment schedule where anthracycline dose was to be modulated according to observed hematological toxicity. Patients with low or low-intermediate IPI (IPI 0-2) and those with intermediate-high or high IPI (IPI 3-5) should receive six or eight courses, respectively. Involved-field radiotherapy was allowed for patients with initial bulky disease or with residual masses. RESULTS: Three hundred and fifty-six patients were registered into the study and randomized. Patients were well balanced among the four study arms in terms of clinical characteristics and prognostic factors. Three hundred and forty-five patients were available for evaluation of study endpoints. At the end of induction therapy complete remission rate was 61%, 5-year failure-free survival (FFS) rate was 40% and 5-year overall survival (OS) rate was 59%; no differences were observed according to treatment arms. Patients in the flexible arm received higher dose intensity of anthracycline (P < 0.001) with no apparent increase in toxicity. However, the flexible schedule was not superior to the fixed one. Patients with IPI 3-5 showed lower response rates (45% vs. 67%: P < 0.0001) and lower 5-year FFS (29% vs. 45%: P < 0.0001) compared to those with IPI 0-2. CONCLUSIONS: six courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL with IPI 0-2, whereas the same regimens are less effective in patients with IPI 3-5, even if two additional courses are delivered. For the latter group of patients innovative approaches are warranted.