Viviana Minardi

Hepatitis B virus reactivation and alemtuzumab therapy

Abstract:  Reactivation of hepatitis B virus infection in subjects receiving cytotoxic treatment for heamatological malignancies occurs in 21–53% of chronic HBsAg carriers and in an unknown number of HBsAg negative subjects harbouring occult HBV infection. Immunotherapy with alemtuzumab, a humanized monoclonal antibody against CD52 epitopes on lymphocytes cells produces deep immunosuppression. We describe two subjects with chronic lymphocytic leukaemia and occult HBV infection who developed a virological and biochemical flare of hepatitis B following immunotherapy with alemtuzumab. One of them developed full blown hepatitis with seroreversion from anti‐HBs to HBsAg after four weeks of alemtuzumab therapy. Lamivudine (100 mg die) achieved a complete clinical recovery and HBV‐DNA clearance from blood within 8 weeks. The second patient (HBsAg and HBV‐DNA seronegative, anti‐HBs and anti‐HBc positive before treatment) was kept under prophylaxis with lamivudine up to three months after alemtuzumab. Two months after withdrawal of lamivudine, clinical and laboratory features of acute hepatitis B developed. Lamivudine therapy was restarted and a prompt recovery was obtained with HBsAg and HBV‐DNA clearance.

Angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive neoplasm clinically characterized by sudden onset of constitutional symptoms, lymphadenopathy, hepatosplenomegaly, frequent autoimmune phenomena, particularly hemolytic anemia and thrombocytopenia, and polyclonal hypergammaglobulinemia. The lymph node histological picture is also distinctive, constituted by a polymorphic infiltrate, a marked proliferation of high endothelial venules, and a dense meshwork of dentritic cells. The neoplastic CD4+ T-cells represent a minority of the lymph node cell population; its detection is facilitated by the aberrant expression of CD10. Almost all cases arbor an EBV infected B-cell population. Patients with AITL have a poor prognosis with conventional treatment, with a median overall survival of less than 3 years. Patients achieving a good clinical response seem beneficiate from a consolidation with high-dose therapy and autologous stem cell transplantation. Constitutional symptoms and autoimmune phenomena, and some times also the neoplastic masses may respond to immunosuppressive or immunomodulatory agents such as thalidomide.

Deoxycoformycin (pentostatin) in the treatment of splenic marginal zone lymphoma (SMZL) with or without villous lymphocytes

Abstract:  Background: Splenic marginal zone lymphoma (SMZL) is an infrequent B‐cell neoplasm that pursues an indolent course. Signs and symptoms, mostly related to hypersplenism, are successfully managed by splenectomy. However, the therapy of patients who are not fit for a surgical procedure or who relapse after splenectomy, is still an unsettled issue. Patients and methods: We report a phase‐II study on 16 patients with SMZL, three therapy naïve and 13 pretreated, all showing systemic symptoms or progressive worsening of peripheral cytopenia, who were treated with pentostatin at a dose of 4 mg/m2 every other week for 6–10 wk. In relapsed patients, the median interval between diagnosis and treatment was 26 month (range: 8–49). Results: Overall, 68% of the patients showed a clinical response. Two out three patients, who received pentostatin as first line therapy, attained a complete response (CR). One CR and seven minor or good haematological responses were recorded in relapsed patients. Treatment toxicity, mostly haematological, proved manageable. With a median follow‐up of 35 month the median overall survival (OS) is 40 month and the median progression free survival (PFS) is 18 month. Conclusion: Our data show that pentostatin administered every other week has a good degree of activity in the treatment of SMZL and suggest that this schedule could be considered a possible therapeutic option for patients who are not fit for splenectomy or have relapsed.

Use of intrapleural bortezomib in myelomatous pleural effusion.

Myelomatous pleural effusion (MPE) is a manifestation of an aggressive course of multiple myeloma (MM) (Iannitto et al, 1988; Alexandrakis et al, 2004) and approximately 80 cases have been reported to date. MM associated with MPE has been related with a poor prognosis and it is often associated with high-risk disease. There is no standard treatment for MPE and the survival is generally <4 months (Kamble et al, 2005). Bortezomib has been shown to have impressive activity in patients with relapsed-refractory MM (Richardson et al, 2005). We describe a case of MPE that was successfully treated with intrapleural plus i.v. bortezomib administration. A 66-year-old, immunoglobulin (Ig) G-k MM male patient, who had progressive disease despite a tandem autologous bone marrow transplantation (doubling of the serum M-component level, 30 g/l), was admitted to our hospital because of severe respiratory distress. A thorax computed tomography (CT) scan revealed a left pleural effusion and a 5-cm paravertebral nodular lesion involving the upper lobe of the right lung. Morphological, flow-cytometric and immunocytochemical analysis of the pleural fluid (Palmer et al, 2000) and an echoguided lung biopsy showed the presence of atypical CD38 IgG-plasma cells (Fig 1A). Pleural fluid electrophoresis (Fig 1B) showed an M-component that was identical to that identified in the serum. The patient received two courses of bortezomib (1Æ3 mg/m) plus dexamethasone (20 mg), i.v., in a 3-week cycle on days 1, 4, 8, and 11; pegylated liposomal doxorubicin (Caelix , Shering-Plough, Milan, Italy) at a dose of 40 mg/m was also administered on day 1 of each cycle. Evacuative thoracenteses were needed twice a week. We observed a 75% reduction of the serum M-component (10 g/l) without any improvement of the pleural effusion formation rate. Pharmacodynamic modelling of bortezomib has shown a dose-dependent proteasome inhibition that is related both to the single dose in mg/m, and to the total dose delivered (Orlowski et al, 2002). We therefore decided to overcome the poor response of pleural MM effusion by increasing the local bortezomib concentration using combined i.v. and intrapleural infusion. The patient gave his informed written consent to the intrapleural administration of bortezomib. Thus, on days 1, 4, 8, and 11 of the next two cycles, after performing an evacuative thoracentesis, we infused half the

Assessment of the frequency of additional cancers in patients with splenic marginal zone lymphoma

Abstract:  Objectives: Solid second primary cancers (SPC) have become an issue of extensive research. The purpose of the present study was to estimate the standardised incidence ratio (SIR) and the absolute excess risk (AER) of SPC in patients with splenic marginal zone lymphoma (SMZL).Methods: We investigated the incidence of additional cancers in 129 patients consecutively diagnosed with SMZL in three Italian haematological centres, asking the cooperating doctors for additional information on initial and subsequent therapies and on the onset and type of second cancers.Results: Twelve SPC were recorded (9.3%); the 3‐ and 5‐yr cumulative incidence rates were 5.5% and 18.3% respectively, with an SIR of 2.03 [95% confidence interval (CI): 1.05–3.56; P < 0.05; AER = 145.81]. Of 12 SPC observed, four were urinary tract neoplasms (SIR, 3.70; 95% CI: 1.01–9.48; P < 0.05; AER = 70.06), four were lung cancers (SIR, 9.16; 95% CI: 1.41–13.25; P < 0.05; AER = 85.50) and the other four were hepatic carcinoma, endometrial cancer, breast cancer and colorectal cancer. Conclusions: Our findings evidence a high frequency of additional cancers in patients with SMZL and suggest that the incidence rate of SPC is significantly different from that expected in the general population. The frequency of cases with urinary tract and lung malignancies in our series is higher than expected. Although confirmatory data are needed, it is our opinion that SMZL patients are at risk of second cancer and should be carefully investigated on diagnosis and monitored during the follow‐up.

Response-guided ABVD chemotherapy plus involved-field radiation therapy for intermediate-stage Hodgkin lymphoma in the pre-positron emission tomography era: a Gruppo Italiano Studio Linfomi (GISL) prospective trial.

PURPOSE In the pre-positron emission tomography era, the Gruppo Italiano Studio Linfomi (GISL) investigated the feasibility and efficacy of a treatment based on a response-tailored number of doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD) courses in 218 intermediate-stage Hodgkin lymphoma patients. PATIENTS AND METHODS Patients with stage I/II showing at least one adverse prognostic factor and stage IIIA without adverse prognostic factors were recruited. Treatment included a first step of 3 ABVD courses, followed by an early-restaging. Patients in CR/CRu received 1 additional ABVD cycle, patients in PR received 3 more ABVD, and nonresponder patients went off study. Involved-field radiation therapy (RT) was recommended on chemotherapy completion. RESULTS The median age was 30 years (range, 15-68 years) and 131 patients (61%) were female. Seven percent of patients were in stage I, 78% in stage II, and 15% in stage III; B-symptoms, bulky tumor and erythrocyte sedimentation rate > 30 were recorded in 20%, 26%, and 43% of cases, respectively. The CR/CRu rate was 62% at early restaging, 72% at the end of chemotherapy, and 95% following RT. With a median follow-up of 74 months (range, 6-193 months), 7-year overall survival, relapse-free survival, and freedom from treatment failure were 91.8% (95% CI, 86%-95.5%), 89.2% (95% CI, 82.8%-93.3%), and 81.8% (95% CI, 75.2%-86.7%), respectively. Patients in CR/CRu on early restaging, receiving 4 ABVD, had an excellent outcome with 7-year RFS and cause-specific survival similar to those of the late responders treated with 6 ABVD (RFS, 87.5% vs. 90.5% and CSS, 96.6% vs. 92.7%, respectively). CONCLUSION The response-guided ABVD program we report, based on standard clinical staging procedures, proved to be feasible and safe in patients with intermediate-stage Hodgkin lymphoma.