Federico Silvestri

Lamivudine allows completion of chemotherapy in lymphoma patients with hepatitis B reactivation.

Reactivation of hepatitis B virus in patients receiving chemotherapy for non‐Hodgkins lymphoma (NHL) may give rise to hepatitis, hepatic failure and death, and prevent further chemotherapy. We report four patients with NHL in whom hepatitis flare‐up was observed after two (three patients) and six (one patient) cycles of chemotherapy. After spontaneous recovery, they were treated with Lamivudine (100 mg/day), which enabled completion of chemotherapy without further hepatitis B reactivation. In one patient, high‐dose chemotherapy and autologous stem cell transplantation was also performed. These data suggest a possible role for Lamivudine in preventing hepatitis B reactivation during chemotherapy administration to chronic carriers of the hepatitis B virus. Moreover, it enabled the completion of both standard and high‐dose chemotherapy in patients with previous hepatitis B reactivation.

HEPATITIS C VIRUS‐RELATED LYMPHOMAS

To date, the available data on the prevalence of hepatitis C virus (HCV) infection among the lymphoproliferative disorders (LPD) consists of 16 Italian studies and seven from other countries. Most of these studies have been published in the last 2 years and the novelty of this topic is also emphasized by the fact that LPD among the extrahepatic manifestations of HCV infection were not included in two papers regarding the natural history of community-acquired (Alter et al, 1992) and transfusion-associated (Seef et al, 1992) HCV infection, nor in two recent reviews (Alter, 1995; Gumber & Chopra, 1995).

Caspofungin as first line therapy of pulmonary invasive fungal infections in 32 immunocompromised patients with hematologic malignancies

Invasive Fungal Infections (IFI) remain a severe and major complication among patients with hematologic diseases, but the recent availability of new antifungal agents (echinocandins and new azoles) have improved the chance of cure. Caspofungin (Cancidas‐Merck) is a large lipopeptide molecule able to inhibit the enzyme complex 1,3‐d‐glucan synthetase; this action specifically damages the fungal cell wall. Caspofungin (CAS) is active, in vitro and in vivo, against most Candida species and Aspergillus species. We report on our experience with this drug as first‐line therapy for proven or probable pulmonary IFI in immunocompromised patients with hematologic malignancies. Thirty‐two consecutive patients (20 males and 12 females, with a median age of 52 yr) have been treated with CAS (27 acute leukemias, 1 chronic leukemia, 3 lymphomas and 1 multiple myeloma). Sixteen patients (50%) had a relapsed or resistant hematologic disease, while 12 patients were in complete remission and 4 were at onset of disease; 8/32 (25%) developed IFI after a hematopoietic stem cell transplant (HSCT) procedure. Seven out of 32 patients (22%) had a proven pulmonary IFI (7/7 Aspergillosis) and 25 (78%) had a probable IFI with pulmonary localization as defined according to international consensus. Thirty‐one patients (97%) had less than 1000 granulocytes/mL at onset of infection and at the start of CAS therapy. The CAS was given at the dose of 70 mg on day 1, followed by 50 mg/day. Median duration of CAS therapy was 20 d (range 8–64); all the 31 neutropenic patients received concomitant granulocyte colony‐stimulating factor (G‐CSF). The overall response rate was 56% (18/32) with 12/18 complete responses and 6/18 partial responses; two patients (6%) had a stable disease. Twelve out of 32 (38%) did not respond and seven died of mycotic infection. Univariate analysis showed that granulocytes recovery (>500/mL vs. <500/mL) and status of hematologic disease (remission/onset vs. refractory/relapsed) were significantly associated to favourable outcome. No clinical adverse events (AE) were reported and only a grades I and II transient increase of serum alkaline phosphatase and/or transaminases occurred in 4/32 (12%) patients. After CAS therapy six non‐responders and six cases with a partial or stable response were rescued with voriconazole. Two out of six patients (33%) in the former group and 6/6 (100%) in the latter obtained a complete resolution of IFI. Our experience suggests an efficacy of CAS, in combination with G‐CSF, as first‐line treatment of proven or probable IFI with pulmonary localization. The drug was well tolerated and there were no significant hepatic AE even in patients receiving CAS with cyclosporine after a HSCT. A significant proportion of non‐responders or partial responders to CAS can be rescued with a subsequent voriconazole‐based therapy.

Impact of hepatitis C virus infection on clinical features, quality of life and survival of patients with lymphoplasmacytoid lymphoma/immunocytoma

BACKGROUND The non-Hodgkins lymphoma (NHL) subgroup most frequently associated with hepatitis C virus (HCV) infection is the lymphoplasmacytoid lymphoma/immunocytoma (Lp-Ic). We have assessed the impact of the infection on the clinical features, quality of life and survival of HCV+ve Lp-Ic patients as compared to its impact in HCV-ve patients. PATIENTS AND METHODS Seventy patients with Lp-Ic consecutively observed over a six-year period were studied. Clinical, virological and histopathological features were recorded at diagnosis. Quality of life was assessed using a scoring system including disease-related symptoms, performance status, working ability, hospital admissions and therapies required. RESULTS Eighteen patients (26%) with HCV infection were identified. Significant differences between those patients and the HCV-ve group included number of symptomatic patients, Hb levels, serum protein levels, entity of the IgM monoclonal component, number of patients with cryoglobulins and with organ (liver, kidney) involvement, and entity and pattern of bone marrow infiltration. Survival rates were similar (P = 0.8383), but the quality-of-life score was significantly worse for the HCV+ve patients (P = 0.002). All anti-HCV Ab+ve patients tested positive for HCV RNA; genotype 2ac was detected in a significant proportion of cases. CONCLUSIONS This study confirms that HCV infection is present in about one-third of patients with Lp-Ic. HCV infection does not seem to affect the overall survival of patients with Lp-Ic, but it affects the clinical expression of the disease, so that the overall quality of life of HCV+ve patients is significantly worse.

Incidence and Diagnosis of EDTA-Dependent Pseudothrombocytopenia in a Consecutive Outpatient Population Referred for Isolated Thrombocytopenia

Among 111 patients referred to our outpatient clinic for isolated thrombocytopenia during a 24‐month period, 17 (15.3%) cases of EDTA‐dependent pseudothrombocytopenia (EDTA‐PTCP) were identified. EDTA‐PTCP represented the second most frequent cause of thrombocytopenia in this population. The diagnosis was confirmed by the following findings: (a) normal platelet numbers immediately after blood withdrawal; (b) progressive fall of platelet counts and evident platelet clumping over time, only in EDTA‐anticoagulated blood. A simple, inexpensive and quick diagnostic method was devised, that consists in evaluating the platelet number in a blood sample anticoagulated with EDTA immediately after blood withdrawl and 4 h later.

Long‐lasting complete remission of hepatitis C virus (HCV) infection and HCV‐associated immunocytoma with alpha‐interferon treatment

Several epidemiological data suggest the involvement of hepatitis C virus (HCV) in the pathogenesis of some histotypes of B‐cell non‐Hodgkins lymphomas, in particular immunocytoma. We report a patient with HCV‐associated immunocytoma, first treated with six courses of fludarabine. A partial response was achieved and subsequent therapy with alpha‐interferon resulted in the clearance of the virus and a long‐lasting complete clinical and histological remission of the lymphoproliferative disease.

Meningeal and cerebral involvement in multiple myeloma patients

Abstract. Cerebral involvement is an unusual complication in multiple myeloma: herein four patients who presented myelomatous meningitis with multiple intraparenchymal lesions or a localized cerebral plasmacytoma are described. Two of these patients relapsed with meningeal involvement and a very limited disease outside the central nervous system after an initial complete remission obtained with induction chemotherapy. In the other two cases, the cerebral tumor appeared during first-line treatment. Cytological examination of the cerebrospinal fluid and magnetic resonance were essential for diagnosis. Different modalities of treatment were used, including intrathecal chemotherapy, cranial irradiation, and systemic chemotherapy with high-dose methotrexate and cytarabine, achieving improvement of neurological symptoms in three of four patients.

BCL-2 immunohistochemical evaluation in B-cell chronic lymphocytic leukemia and hairy cell leukemia before treatment with fludarabine and 2-chloro-deoxy-adenosine.

Bcl-2 overexpression has been shown to be associated with several malignancies, including B-cell chronic lymphocytic leukemia (CLL) and non-Hodgkins lymphomas (NHL), mainly low-grade and follicular in type. It has as yet not been described in hairy cell leukemia (HCL). In 30 patients with CLL and 14 with HCL who were consecutively selected for treatment with purine analogues (Fludarabine in CLL and 2-chloro-deoxy-adenosine in HCL), we evaluated bcl-2 oncoprotein expression in leukemic cells on marrow sections that were taken before treatment and stained immunohistochemically with a monoclonal antibody (Dakopatts 124 clone), by the avidin-biotin-peroxidase method. All samples were found to be bcl-2 positive, with a staining intensity that was moderate to strong in CLL and weak to moderate in HCL. 83% of CLL and 100% of HCL patients were responsive to purine analogues. These findings show that bcl-2 is overexpressed in almost all cases CLL and HCL and that bcl-2 overexpression does not predict a poor response to purine analogues, which are believed to induce apoptosis.

The role of granulocyte colony-stimulating factor (filgrastim) in maintaining dose intensity during conventional-dose chemotherapy with ABVD in Hodgkin's disease.

Background The aim of the study was to evaluate the role and potential benefit of granulocyte colony-stimulating factor (G-CSF, Filgrastim), administered following cytotoxic chemotherapy with the ABVD regimen in Hodgkins disease, in maintaining cycle schedule and dose intensity and in decreasing neutropenia and number of infections. Patients and Methods Twenty-two patients affected by high-risk Hodgkins disease (14 localized and 8 diffuse), aged 15 to 69 years (median, 34), were given ABVD chemotherapy for a total of 6 courses (for the purpose of this study, each single course of chemotherapy was considered as two 15-day periods). No patient was given G-CSF after the first cycle. After each cycle, G-CSF was administered only for: 1) absolute neutrophil count < 1 × 109/L between cycles; 2) delay in cycle schedule due to an absolute neutrophil count < 1 × 109/L on the planned day of treatment; or 3) fever or a documented infection, regardless the absolute neutrophil count. Once administered, G-CSF was maintained in the subsequent cycles. Results Seventeen of 22 patients (77%) required the administration of G-CSF (5 μg/kg b.w.; a median of 5 doses/cycle); most of them (13/17) before the 5th dose of chemotherapy. The main reason for introducing G-CSF into therapy was neutropenia during the interval between courses (n = 4) or on the planned day of treatment (n = 11). Comparing 112 courses where G-CSF was not administered with 124 where it was, in the latter group we observed: 1) a significantly lower (P = 0.0002) incidence of cycle delays (0 vs 13), with a median delay of 7 days (5 to 11). The main reason for cycle delay was neutropenia (n = 13); 2) a greater dose intensity delivered to the patients while on G-CSF (100% vs 95.2±8.8%; P = 0.0001); 3) an absolute neutrophil count significantly higher at day 8 (P<0.0001) and day 15 (P< 0.0001); 4) a significantly lower (P = 0.0003) incidence of neutropenia (2 vs. 17). No difference in the incidence of infections was observed between the two groups of cycles (P = 0.5889), but the duration and severity of the same were greater during chemotherapy without G-CSF, requiring antibiotic therapy and causing cycle delay. Conclusions In conclusion, our data suggest the use of Filgrastim in Hodgkins disease also during conventional-dose chemotherapy with ABVD. It is not required from the first dose of therapy, but as soon as neutropenia appears between cycles or on the planned day of treatment. Then, its use allows maintenance of the chemotherapy schedule and dose intensity. It also decreases frequency, duration and severity of neutropenia and its sequelae.

Combined therapy with Fludarabine and Cyclophosphamide in relapsed/resistant patients with B‐cell chronic lymphocytic leukaemia and non‐Hodgkin's lymphomas

To the Editor: Used as a single agent, Fludarabine (Fluda), a fluorinated purine analogue, proved to be highly effective in the treatment of patients with B-cell chronic lymphocytic leukaemia (CLL) (1-2) and low-grade non-Hodgkin’s lymphomas (NHL) (3-4). In these diseases Fluda is able to induce a 7 0 4 0 % overall response with 30-50% of complete responses (CR) in untreated patients and a 20-50% overall response with 10-15% of CR in previously treated patients with progressive or resistant disease. In an attempt to improve the therapeutic results, especially for patients previously treated, Fluda was tested in combination with other cytotoxic drugs (5-6), obtaining better results even in patients with poor prognosis. Herein we report our initial experience on the use of Fluda combined with Cyclophosphamide (CTX) in 16 poor prognosis patients with CLL (6 cases) and NHL (10 cases), relapsed or resistant to previous treatment. Five of the 6 CLL patients were previously treated with Fluda alone (6 courses), achieving a transient response (median 7 months, range 4-8 months). The NHL patients were previously treated with one or more antracyclinecontaining regimens and only one had also received Fluda. Patients’ features before therapy are reported in Table 1. The therapeutic schedule consisted of the association of Fluda 25 mg/m2 and CTX 300 mg/m2 daily for 5 d, to be repeated every 28d to a maximum of 6 courses (depending on response rate and compliance). Patients’ evaluation before and after treatment was performed by means of physical examination, blood cell count and differential, thoracic X-ray, abdomen ultrasound or computed tomagraphy scan and bone marrow biopsy. For the CLL patients the response to therapy was defined as complete (CR), partial (PR) or no response (NR) according to the NCI criteria (7). For the NHL patients the response to therapy was defined as complete in case of complete disappearance of all signs of disease, .as