Giulia Cervetti

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 Hodgkins 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.

Unexpected cardiotoxicity in haematological bortezomib treated patients

Bortezomib is an antitumor compound that inhibits proteasome activity. It is able to impair the activation of nuclear factor (NF)-jB, blocking the degradation of inhibitory jB (IjB), which is required for NF-jB translocation into the nucleus and activation of target genes. NF-jB is important for cell survival, regulating the expression of genes involved in apoptosis, such as BCL2 and BCL2L1, cell cycle progression, inflammation and angiogenesis (Richardson et al, 2003). In 2006, we treated 69 patients with bortezomib, either alone or as combination therapy. Bortezomib therapy is known to be associated with neurological side effects and thrombocytopenia (Richardson et al, 2003); however, we noticed an unexpected increase of cardiac complications, ranging from heart failure to onset of arrhythmias. Only one single case of heart failure (Voortman & Giaccone, 2006) and one asymptomatic arrhythmia (Berenson et al, 2007) following bortezomib therapy have been reported to date. All except one of our bortezomib-treated patients were receiving at least a second line therapy, and some of them had previously received anthracycline-containing regimens. Eight (11Æ6%) of the 69 patients developed serious cardiac side effects requiring medication, hospitalisation or the implant of a pacemaker (see Table I). All patients underwent cardiovascular screening before receiving bortezomib and no clinically significant abnormalities were present. The only conditions that were identified as common to all the patients were bortezomib administration and age >60 years. All eight patients who experienced cardiotoxicity underwent at least four cycles of bortezomib, strengthening the hypothesis of a direct connection with the drug. Each cycle included bortezomib 1Æ3 mg/m on days 1, 4, 8 and 11 and the recycling period was 3 weeks. The onset of cardiac symptoms was never recorded before a cumulative dose of 20Æ8 mg/m of bortezomib. The ubiquitin-proteasome system is responsible for nonlysosomal degradation of intracellular proteins, including key regulators of cell cycle, angiogenesis and apoptosis, and transcription factors, which regulate crucial mechanisms of plaque formation and rupture. Additionally, the presence of a reduced proteasome activity is associated with an increased rate of apoptosis in smooth muscle cells, determining atherosclerotic plaque instability by weakening of the fibrous cap and enlargement of the necrotic core (Versari et al, 2006). Furthermore, NF-jB activation plays an essential role in the intracellular signal transduction of the second window of protection of delayed ischaemic preconditioning in the myocardium, leading to myocardial cytoprotection (Jancso et al, 2005). Therefore, bortezomib may simultaneously cause atherosclerotic plaque progression and tendency to rupture, and facilitate ischaemic heart complications by reducing/abrogating myocardial preconditioning. Additionally, although bortezomib was found to reduce the onset of delayed arrhythmias following coronary ligation in the canine model by upregulating

Rituximab as treatment for minimal residual disease in hairy cell leukaemia

Abstract:  Purine analogues have dramatically improved the outcome of patients affected by hairy cell leukemia (HCL), although complete eradication of disease was achieved in few cases. The purpose of this study was to evaluate the role of Rituximab in eradicating minimal residual disease (MRD) in HCL patients after a pre‐treatment with 2‐chloro‐deoxy‐adenosine (2‐CdA). Ten patients received four cycles of Rituximab after administration of Cladribrine. Before starting anti‐CD20 antibody, two patients were in complete remission, six in partial remission and two showed no significant response to Cladribrine. All cases resulted IgH‐positive. Median time from the last 2‐CdA infusion was 5.7 months. Eight of 10 patients [four in partial remission (PR), two in complete remission (CR) and two unresponsive after 2‐CdA] were evaluable for response. Two months after the end of anti‐CD20 therapy, all evaluated patients presented a complete haematological remission. Moreover, Rituximab increased percentage of molecular remission up to 100% 1 yr after the end of treatment. Interestingly, in all cases but one, including those persistently polymerase chain reaction (PCR)‐positive, semi‐quantitative molecular analyses showed MRD levels lower than those found before Rituximab administration. Toxicity was very mild. The present results not only confirm the therapeutic effect of Rituximab, but also show its relevance in eradicating MRD in HCL.

Quantitative molecular evaluation in autotransplant programs for follicular lymphoma: efficacy of in vivo purging by Rituximab

Summary:The main aim of this paper was to compare results of Genescan and real-time PCR methods in order to detect contamination in harvests from patients with follicular lymphoma. The secondary goal was to evaluate the efficacy of Rituximab as an in vivo purging agent. A total of 23 patients had been treated with CHOP followed by either high-dose therapy (12 patients) or high-dose plus Rituximab (11 patients), both followed by autologous transplantation. Results show that 86% of harvests from patients treated whith Rituximab were PCR-negative compared to 14.3% from controls. Real-time PCR was more sensitive than Genescan PCR; quantitative analysis revealed a correlation between the amount of contamination in the harvests and relapse after transplantation. Whereas all patients reinfused with negative aphereses achieved complete remission and showed a significantly better 5-year PFS (100%) compared to those reinfused with contaminated samples (41%), a very low amount of contamination does not appear to negatively affect outcome, suggesting that determination of a cutoff in the contamination level of harvests could be useful. Results suggest that real-time PCR is superior to Genescan PCR to select transplantable harvests and confirm the ability of Rituximab as an in vivo purging tool for follicular lymphoma.

Significant efficacy of 2-CdA with or without rituximab in the treatment of splenic marginal zone lymphoma (SMZL)

BACKGROUND Splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes is an indolent lymphoma that typically affects elderly patients. Treatment is required in symptomatic cases. Splenectomy remains one of the first-line options in patients fit for surgery. The best therapeutic strategy has not yet been identified. Among different possible chemotherapeutic approaches, purine analogues, alone or in association with rituximab, seem to be a valid therapeutic choice. PATIENTS AND METHODS Fifty SMZL patients were treated with cladribine with or without anti-CD20 mAb. RESULTS Forty-six of 50 patients were assessable for response. Overall response rate was 87%: 24 of 46 patients (52%) achieved a complete hematological response (CR), 16 of 46 (35%) a partial response and 6 (13%) were unresponsive. Interestingly, 15 of 24 cases (62%) in CR also achieved a molecular remission. CONCLUSIONS The present results indicate that this schedule is a valid therapeutic approach in SMZL. Addition of rituximab significantly improved quality of response and consequently the outcome of the disease.

Rituximab as treatment for minimal residual disease in hairy cell leukaemia: extended follow-up

Hairy cell leukaemia (HCL) is a rare chronic lymphoproliferative disorder accounting for about 2% of adult leukaemias. Malignant cells present features of mature activated B-lymphocytes with bright expression of light-chain-restricted surface immunoglobulin (sIg), expression of numerous clonally related heavy-chain isotypes, IGHV mutation and co-expression of mature B cell CD markers. Treatment is indicated in the presence of significant cytopenia, symptomatic splenomegaly, recurrent infection or systemic symptoms. In recent years, therapeutic advances have brought about drastic changes in HCL prognosis. Purine analogues, especially 2-chlorodeoxyadenosine (Cladribine), drastically improved the survival rate, although complete eradication of disease can be rarely achieved (Piro et al, 1990; Tallman et al, 1996). Minimal residual disease (MRD) can be detected either by polymerase chain reaction (PCR) or immunohistochemical techniques on bone marrow samples of patients in complete haematological remission after purine analogue therapy. The persistence of MRD could thus explain the high relapse rate observed in HCL patients after long-term follow-up from the end of induction therapy (Wheaton et al, 1996). Rituximab could represent one attractive option in relapsed cases, because hairy cells typically express high levels of CD20 (Juliusson et al, 1994; Hoffman & Auerbach, 2000; Hagberg & Lundholm, 2001). The optimal schedule has not yet been defined, but some data suggest that extended dosing may improve patient outcome (Thomas. et al, 2003). Moreover, Rituximab could play an interesting role even in eradicating MRD (Cervetti et al, 2004; Ravandi et al, 2006). In our Institution, between May 2002 and November 2006, 27 HCL patients (25 male and 2 female; median age 60 years, range 39–72 years) were treated with anti-CD20 after a pretreatment with Cladribrine. Patients were considered eligible for the study if in partial remission or with persistence of MRD after induction. Other inclusion criteria were: age >18 years; life expectancy >6 months; absence of renal, hepatic and respiratory failure; written informed consent. Baseline clinical characteristics of patients are summarized in Table I. Cladribrine was started if patients presented at least one of the following indications: neutropenia (absolute neutrophil count, <1Æ5 · 10/l), anaemia (haemoglobin level, <100 g/l), thrombocytopenia (platelet count, <100 · 10/l), symptomatic splenomegaly, constitutional symptoms or documented repeated infections. In 17 patients older than 60 years, Cladibrine was administered IV at a dose of 5 mg/m/weekly for a total of six cycles, whereas in 10 younger patients, Cladribine was infused at the dose of 5 mg/m/d for five consecutive days. All patients received acyclovir, fluconazole and cotrimoxazole as antiinfective prophylaxis until 8 weeks after completion of Cladribine administration. Two months after the end of treatment, patients were evaluated for early response. Response criteria were those defined by the National Cancer Institute Working Group. At the time of enrolment in the study, overall response after Cladribrine was 89% [complete remission (CR) 26%, partial remission (PR) 63%; three cases were unresponsive]. The median time between the last Cladribine infusion and the beginning of this protocol was 4Æ3 months (range 1Æ5– 113 months). Minimal residual disease was evaluated by repeating PCR assays. PCR analyses were performed on DNA extracted from mononuclear cells separated by Ficoll/Hypaque gradient, as previously reported (Cervetti et al, 2004). By this method, all cases were proven to be still PCR-positive after induction. After demonstration of persistent MRD or detectable clinical disease, patients were treated by Rituximab (375 mg/m once a week for four doses). Statistical calculations were performed using the Statistical Package for the Social Sciences (spss) for Windows, release 15

The c.480C>G polymorphism of hOCT1 influences imatinib clearance in patients affected by chronic myeloid leukemia.

The aim of the study was to investigate any possible influence of polymorphisms of transmembrane transporters human organic cation transporter 1 (hOCT1), ABCB1, ABCG2 on imatinib pharmacokinetics in 33 men and 27 women (median age and range, 56 and 27–79 years, respectively) affected by chronic myeloid leukemia. A population pharmacokinetic analysis was performed to investigate imatinib disposition in every patient and the role of transporter polymorphisms. Results showed that the α1-acid glycoprotein and the c.480C>G genotype of hOCT1 had a significant effect on apparent drug clearance (CL/F) being responsible, respectively, for a 20% and 10% decrease in interindividual variability (IIV) of CL/F (from 50.1 up to 19.6%). Interestingly, 25 patients carrying at least one polymorphic c.480 G allele had a significant lower CL/F value with respect to the 35 c.480CC individuals (mean±s.d., 9.6±1.6 vs 12.1±2.3 l h−1, respectively; P<0.001). In conclusion, the hOCT1 c.480C>G SNP may significantly influence imatinib pharmacokinetics, supporting further analyses in larger groups of patients.

Characterization of Ph‐negative abnormal clones emerging during imatinib therapy

Imatinib is a tyrosine kinase‐specific inhibitor widely used for the treatment of chronic myeloid leukemia (CML). Studies reported the occurrence of additional cytogenetic abnormalities in the Philadelphia chromosome (Ph)‐negative cell population emerging after treatment‐induced suppression of the Ph‐positive clone. These abnormalities were described in a relatively high proportion of patients treated with imatinib compared with the anecdotal reports of similar cases in patients treated with other drugs. However, the origin of these abnormalities as well as their biological and clinical significance are unknown.

Is lithium able to reverse neurological damage induced by vinca alkaloids

Summary. Lithium (Li) actively antagonises the inhibiting action of vinca alkaloids on human leukocyte chemotaxis; it proved to be related to the activation of microtubular system, possibly mediated by its inhibiting effect on cyclic AMP.Vinca alkaloids induce peripheral neuropathy and muscle damage. The molecular basis of this neurotoxicity has not been fully explained, but a possible role of neurofibrillary degeneration has been reported. We studied both in animals and in humans, whether Li is able to antagonise vinca alkaloid neurotoxicity.

Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: A retrospective analysis of real-life practice in Italian hematology departments

The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine-cyclophosphamide-rituximab (FCR). FCR regimen results in a significant myelosuppression and high rates of early and late infections especially in elderly patients. German CLL study group compared FCR vs. bendamustine-rituximab (BR) in fit untreated patients. The response rates with BR or FCR were comparable, BR could be an alternative 1st-line treatment for elderly patients. Here we report retrospective data of 70 elderly (≥65 years) CLL patients from 12 Italian centers treated with BR as front-line therapy. The primary end points were overall response rate (complete remission/partial remission) and safety. Forty-seven males and 23 females, with a median age of 72 years, were included in the study. Eight patients were unfit for CIRS. The OR rate was 88.6% (31.4% CR and 57.2% PR). Progression free survival, treatment free survival and overall survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only del17 was independent unfavorable parameter on the response rate and PFS. Our results indicate that BR front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a bendamustine dose reduction until 70 mg/m2.