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Background and Objectives: Recently, a chimeric monoclonal antibody (MoAb) directed against the CD20 antigen (rituximab) has been successfully introduced in the treatment of several CD20-positive B-cell neoplasias and particularly of follicular lymphomas. Based on these premises we evaluated the efficacy and the toxicity of chimeric anti-CD20 monoclonal antibody (MoAb) in relapsed/progressed hairy cell leukemia (HCL)., Design and Methods: Ten patients with relapsed/progressed HCL entered the study. Eight patients were males and two females with a median age of 55 years (range 41-78) and all of them had been previously treated with 2-chlorodeoxyadenosine and/or deoxycoformycin and a-interferon. Two out of 10 patients were anemic (Hb < 10 g/dL), 4 thrombocytopenic (Plt < 100 x 10(9)/L), 3 had fewer than 1.0 x 10(9)/L neutrophils and 3 had circulating hairy cells (HC). All patients received 375 mg/m2 i.v. of anti-CD20 MoAb once a week for 4 doses., Results: All patients were evaluable for response, one patient showing a complete remission and 4 a partial response. Adverse reactions, such as fever, chills, bone pain, hypotension and thrombocytopenia, were transient and mild (grade 1-2) and occurred only during the first course of treatment. One month after the last infusion, patients who had had anemia, neutropenia or thrombocytopenia, recovered normal peripheral blood values. Circulating HC also disappeared within one month. Immunostained bone marrow biopsies were checked 1, 3 and 6 months after the end of therapy and in 5 out of 10 patients a >50% reduction of bone marrow HC infiltration was recorded., Interpretation and Conclusions: On the basis of these preliminary results observed in 10 patients with progressed HCL, it appears that treatment with anti-CD20 MoAb is safe and effective in at least 50% of patients, particularly in those with a less evident bone marrow infiltration (50%) and in those previously splenectomized.

Background and Objectives: Our aim was to identify risk factors in adults with diffuse large cell lymphoma at first relapse., Design and Methods: We studied 474 patients observed at 45 centers in Italy. Median time from diagnosis to relapse was 395 days, median age at relapse was 55 years and median follow-up from relapse was 3.3 years. Salvage therapy consisted of polychemotherapy in 79% of patients, monochemotherapy and/or radiotherapy and/or surgery alone in 16%, and palliative therapy in 5%. Salvage treatment was intensified with high-dose chemotherapy + stem cell transplant in 20% of patients. OS and PFS were compared by sex, International Prognostic Index at diagnosis, histology, B/T phenotype, initial treatment, salvage therapy, and features at relapse: time from diagnosis, LDH, stage, performance status and bone marrow involvement. Cox models, adjusted for salvage therapy, were performed with factors related to overall survival (OS) and progression-free survival (PFS)., Results: Overall response (complete + partial) was 63%, OS at 3 years 35% and PFS at 3 years 26%. Relapse within 12 months from diagnosis, elevated serum lactic dehydrogenase (LDH), advanced stage and poor performance status were independent adverse factors for OS and PFS. The cumulative number of adverse factors is proposed as prognostic index for DLCL at first relapse since it identifies risk groups (p<0.0001) and has been validated (p=0.01). Moreover, it predicts OS and PFS in the selected group of patients with a responsive relapse (p<0.0001)., Interpretation and Conclusion: Delay from initial diagnosis, LDH, stage and performance status at relapse should be balanced in comparative studies of salvage therapy of adults with DLCL. Patients with more than 2 adverse factors are one third of all cases and deserve more effective salvage treatments.

Background and Objectives: To assess the efficacy and toxic profile of the NAEPP protocol, a regimen including vinorelbine, epirubicin and prednisone, in a particularly troublesome subset of patients: pretreated elderly patients with aggressive non-Hodgkin's lymphoma (NHL)., Design and Methods: From November 1998 to January 2000, 20 pretreated patients who had all relapsed after first-line VNCOP-B chemotherapy were enrolled in a phase II trial and treated with the NAEPP regimen: vinorelbine (25 mg/m(2) i.v. on days 1 and 8), epirubicin (40 mg/m(2) i.v. on days 1 and 8), and prednisone (40 mg/m(2) on days 1 and 8) with granulocyte colony-stimulating factor administered at 5 mg/kg/day on days 2-5 and days 9-12. Chemotherapy was repeated every 4 weeks for a total of 6 cycles., Results: Six (30%) patients achieved complete remission (CR) and 7 (35%) had partial responses (PR), giving an overall response rate of 65%. The response rate was not affected either by type of relapse presentation (nodal versus nodal plus extranodal), presence of bulky disease, or time of relapse. No major toxic effects were recorded., Interpretation and Conclusions: These preliminary data suggest that the NAEPP regimen is an effective combination with a low toxicity profile in elderly pretreated patients with aggressive NHL. Further trials using NAEPP as a consolidation phase following first-line treatment are needed to establish the advantage in terms of CR rate and relapse-free survival in these patients.

Background and Objectives: Primary mediastinal large B-cell lymphoma (PMLBCL) with sclerosis has recently been recognized as a specific clinical and pathologic entity for which the best therapeutic approach seems to be a combination of chemotherapy and radiotherapy., Design and Methods: Between 1989 and 1998, 89 previously untreated patients with PMLBCL with sclerosis were treated with a combination of a third-generation chemotherapy regimen (MACOP-B) and mediastinal radiation therapy. The response evaluations were examined after chemotherapy and at the end of radiotherapy., Results: Twenty-three (26%) patients achieved a complete response (CR) and 59 (66%) obtained a partial response (PR) after the MACOP-B regimen. After radiation therapy, 55/59 (93%) of the patients in PR achieved CR. The CR rate at the end of the treatment was 88% (78/89). Only 7 (8%) patients were non-responders. Among the 78 patients who obtained a CR there were 7 (9%) relapses in a median follow-up of 5 months (all relapses occurred within 9 months); the other 71 patients are currently in continuous CR with a median follow-upof 45 months (range, 4-110 months). Projected overall survival was 86% at 9 years; the relapse-free survival curve of the 78 patients who achieved CR was 91% at 9 years., Interpretation and Conclusions: In patients with PMLBCL with sclerosis, combined modality treatment using the MACOP-B chemotherapy regimen and radiation therapy induces a good remission rate with the patients having a greater than 90% chance of surviving disease-free at 9 years. Radiotherapy often plays a pivotal role in obtaining CR status.

Background and Objectives: The REAL/WHO classification constitutes a new tool for the better understanding and treatment of malignant lymphomas. The authors focus on the key features of aggressive B- and T-cell lymphomas, aiming to contribute to the cross-talk between pathologists and clinicians., Data Sources and Methods: Each lymphoma entity is analyzed on the basis of the most representative contributions in the literature and the authors' experience gained in studying more than 20,000 lymphoid tumors over a 20-year period., Results: Guidelines for diagnosis and areas of interest for future clinico-pathologic studies are identified and discussed. Within this context, selected data obtained by the application of novel markers are presented., Interpretation and Conclusions: The present know- ledge and organization of malignant lymphomas now make the development of tailored therapies a feasible goal.

Background and Objectives: The REAL/WHO classification constitutes a new tool for the better understanding and treatment of malignant lymphomas. The authors focus on the key features of B-cell lymphomas with an indolent behavior, aiming to contribute to the cross-talk between pathologists and clinicians., Data Sources and Methods: Each lymphoma entity is analyzed on the basis of the most representative contributions in the literature and the authors' experience gained in studying more than 20,000 lymphoid tumors over a 20-year period., Results: Guidelines for diagnosis and areas of interest for future clinico-pathologic studies are identified and discussed. Within this context, selected data obtained by the application of novel markers are presented., Interpretation and Conclusions: The present know- ledge and organization of malignant lymphomas now make the development of tailored therapies a feasible goal.

Background and Objectives: A study update to assess long-term survival following fludarabine salvage treatment in previously treated patients with chronic lymphocytic lymphoma (CLL)., Design and Methods: From September 1992 to December 1995, 74 patients with advanced, relapsing B-cell CLL were enrolled in the study. Fludarabine was given for 5 consecutive days at the dose of 25 mg/m2/day in a 30 min infusion. Treatment was repeated every 28 days for a maximum of 6 courses.E RESULTS. Nineteen (26%) patients achieved a complete response (CR) and 20 (27%) patients had a partial response (PR), giving an overall response rate of 53%. The median overall survival was 68 months, and there was a strong negative correlation with the number of previous treatments. The median time to progression was 18 months for patients who achieved a CR and 12 months for those with a PR., Interpretation and Conclusions: The results obtained with fludarabine alone in this subset of CLL patients indicate the existence of a conspicuous disease-free survival period. This time window could be used to consolidate the initial response with either biological approaches or high-dose therapeutic strategies such as autologous bone marrow transplantation, with the aim of eventual eradication of the disease.

Background and Objectives: To assess the efficacy and the toxic profile of gemcitabine, a novel pyrimidine antimetabolite active against several solid tumors, we carried out a study in heavily pretreated Hodgkin's disease (HD) patients., Design and Methods: From May 1997 to January 1999, 14 pretreated patients (10 relapsed and 4 refractory to previous treatments) were enrolled in a phase II trial and treated with gemcitabine. The drug was given on days 1, 8 and 15 of a 28-day schedule at a dose of 1,200 mg/m2 intravenously for a total of 6 cycles., Results: Two (14%) patients achieved complete remission (CR) and 4 (29%) had partial responses (PR), giving an overall response rate of 43%. In the relapsed subset there was an overall response rate of 50% with 2 CR and 3 PR. Among the refractory patients there was only 1 PR (25%). Both patients who had relapsed after autologous bone marrow transplant achieved a response (1 CR and 1 PR). No major toxic effects were recorded., Interpretation and Conclusions: These data suggest that gemcitabine is an effective drug with a low toxicity profile in patients with heavily pretreated HD. Further trials using gemcitabine in combination with other conventional drugs are needed.

Background and Objectives: The management of patients with hairy cell leukemia (HCL) has evolved significantly over the past two decades. In fact, both 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2-CdA) induce complete response (CR) in the majority of the patients with HCL. However, fewer data exist on the long-term follow-up of patients who have undergone the characteristically brief exposure to 2-CdA therapy. Thus, it is important to evaluate such long-term outcome data in order to increase understanding of the efficacy of this agent in the management of HCL., Design and Methods: We reviewed the long-term follow-up data of 23 HCL patients pretreated with a-interferon and then treated with 2-CdA administered as a single continuous IV infusion for 7 days at the dose of 0.1 mg/kg/day in our institute between January 1991 and February 1992., Results: Of 23 patients, 19 (83%) achieved a CR and 4 (17%) a partial response (PR), with an overall response rate of 100%. After a median follow-up of 102 months (range: 96-108), there have been 9 (39%) relapses. In the PR subset 100% of patients relapsed within the first 45 months of follow-up. In the group of patients who obtained a CR, 26% relapsed; all these relapses occurred between 54 and 86 months. Overall, the median time to relapse was 54 months (range: 16-86). All relapsed patients were re-treated with 2-CdA at the dose of 0.15 mg/kg/day for 5 days in a 2-hour infusion, and 67% and 22% then obtained CR or PR, respectively. The median duration of this second response was 48 months (range: 22-80). All but one of these patients are still maintaining the second response to 2-CdA. The 9-year overall and the relapse-free survivals are 91% and 70%, respectively., Interpretation and Conclusions: In HCL patients a single dose of 2-CdA induces a long-term CR with a 9-year survival > 90%. Over 50% of patients appear to be clinically cured by this procedure, but the lack of a long-term plateau in the relapse-free survival curve means caution on this point is still warranted.

Background and Objectives: No specific chemotherapy regimens have yet been recommended for elderly Hodgkin's disease (HD) patients. We investigated the therapeutic efficacy and toxicity of the three-drug-combination VBM (vinblastine, bleomycin, and methotrexate) regimen in a group of 19 elderly HD patients., Design and Methods: Vinblastine (6 mg/m(2) i.v.), bleomycin (10 mg/m(2) i.v.) and methotrexate (25 mg/m(2) i.v.) were administered on days 1 and 8. Chemotherapy was repeated every 28 days for a total of 6 cycles. Local radiotherapy was given only to patients who presented bulky disease at the time of diagnosis. Of the 19 patients, 13 patients had stage II, 2 stage III, and 4 stage IV disease; the median age was 68 years (range 60 to 75)., Results: Of the 19 patients, 15 (79%) achieved complete response (CR) and 3 (16%) partial response, while the remaining patient showed no benefit from the treatment. With a median follow-up of 48 months, the estimated 5-year relapse-free survival was 79%, and overall survival was 64%. Hematologic grade 3-4 toxicity was seen in only 1 (5%) patient; no severe non-hematologic side effects or deaths were associated with the administration of the VBM regimen., Interpretation and Conclusions: These preliminary data indicate that the VBM regimen provides a safe and effective therapeutic option for elderly patients with untreated HD.

Background and Objective: A prospective study to evaluate the role of fludarabine alone or in combination with idarubicin in untreated patients with mantle cell lymphoma (MCL)., Design and Methods: Twenty-nine untreated patients with mantle cell lymphoma were stochastically treated with intravenous fludarabine at a dose of 25 mg/m(2)/day for 5 days (11 patients) or with a combination of fludarabine and idarubicin (FLU-ID) (fludarabine 25 mg/m(2) i.v. on days 1 to 3 and idarubicin 12 mg/m(2) i.v. on day 1 (18 patients). For both regimens, cycles were given at three-week intervals for a total of six courses. According to the International Prognostic Index, the most part of high-intermediate and high risk factor patients were in the FLU-ID subset: 7 (39%) patients vs. 2 (18%) in the fludarabine alone subset., Results: Of the 29 patients, 8 (28%) obtained a complete response and 10 (35%) a partial response, with an overall response rate of 63%. The remaining 11 (37%) patients did not respond to the therapy. The overall response rates were 64% (7 patients) in the fludarabine group and 61% (11 patients) in the FLU-ID group. The complete response rate was 27% (3 patients) for fludarabine and 28% (5 patients) for FLU-ID. The toxicity was mild in terms of neutropenia and infections, and no fatalities occurred due to drug-induced side effects., Interpretation and Conclusions: These results suggest the efficacy of fludarabine alone or in combination with idarubicin in MCL patients. It will be important to increase this experience and to assess other fludarabine-containing regimens, in particular with cyclophosphamide plus idarubicin and with mitoxantrone and or cyclophosphamide, to test the true role of this approach in MCL.

Background and Objective: To examine the long-term clinical course and prognostic factors of patients with advanced aggressive non-Hodgkin's lymphoma (NHL) treated with third-generation regimens as front-line chemotherapy., Design and Methods: A total of 348 patients aged <60 years received MACOP-B or F-MACHOP regimen between September 1988 and August 1993 for advanced stage aggressive NHL., Results: Of these, 249 (71.5%) obtained a complete response (CR); 65/249 (26%) subsequently relapsed. The CR rates for MACOP-B and F-MACHOP were 70.5% and 72%, respectively, while the relapse-free survival rates (RFS) at 9 years were 66% and 74%, respectively. The overall survival rate at 9 years was 61% for MACOP-B and 67% for F-MACHOP patients. Of the relapses, 78.5% were early (<24 months) and 21.5% late. Eleven out of 65 (17%) patients are in continuous second CR with a median follow-up of 45 months; most of them have been salvaged with high-dose therapies. The validity of the International Prognostic Index was confirmed in long-term analysis., Interpretation and Conclusions: With a 9-year RFS, it is possible to consider cured 50% of the patient with aggressive NHL treated with a third-generation regimen. About a quarter of the CRs relapse and late relapse occurs in roughly 20% of all relapsed patients. In these patients high-dose chemotherapy followed by autologous bone marrow or hematopoietic stem cell transplantation seems to be a very reliable approach in terms of long-term second CR. Finally, the IPI score maintains its pivotal role in terms of stratifying patients according to different risk subsets also in long-term analysis.

Background and Objective: Fludarabine has shown a definite clinical activity in B-cell chronic lymphocytic leukemia (CLL). If the effects of this drug could be potentiated, it could be useful in order to obtain complete remissions. In this study we evaluated the effects of the combination of fludarabine and gemcitabine, a deoxycytidine analog that has shown both in vitro and in vivo activity against a variety of solid tumors., Design and Methods: CLL cells from 10 patients were cultured in vitro in the presence of fludarabine (0.5-1,000 microg/mL) and gemcitabine (0.1-5,000 microg/mL), both alone and in different combinations. Cytotoxic activity was tested by the XTT colorimetric assay. Furthermore we evaluated BCL-2 protein expression and, subsequently, the induction of apoptosis at baseline and after exposing cells to different concentrations of fludarabine and gemcitabine., Results: The IC(50) of fludarabine and gemcitabine on CLL cells was 550 and 1,100 microg/mL, respectively, in our series of samples; the cytotoxicity of either drug was not influenced by the percentage of BCL-2 positive cells in the same sample. The addition of gemcitabine increased fludarabine-induced cytotoxicity; however, isobologram analysis of the data showed synergism only when lower doses of gemcitabine were combined to fludarabine. Induction of apoptosis reflected this pattern of activity., Interpretation and Conclusions: Gemcitabine was able to increase the activity of fludarabine only when low doses of the former were employed. As both compounds incorporate into DNA blocking chain elongation, our results could be explained by the drugs interfering at that level. The possibility of potentiating the effects of fludarabine with low doses of gemcitabine renders this combination promising in view of an in vivo use.

Background and Objective: With the development and refinement of guidance modalities for percutaneous biopsies, many investigators have reported studies supporting the role of guided core needle biopsy in the diagnosis of mediastinal lymphoma. The aims of this report are to evaluate the efficacy of findings at core needle biopsy of mediastinal masses on patient care and define the key determinants of clinical success., Design and Methods: Fluoroscopy-guided (in 75 patients) and computed tomography-guided (in 8 patients) core needle biopsies were performed in 83 patients with mediastinal lymphoma: all but one of the patients were at first diagnosis. All the biopsies were performed using a Menghini needle (from 1.2 mm to 1.8 mm). In the vast majority of cases the 1.8 mm gauge was employed., Results: The overall sensitivity for the diagnosis of lymphoma was 81% (67/83 cases). In the remaining 16 patients the lymphoma diagnosis was reached either by mediastinoscopy (11 cases) or anterior mediastinotomy (3 cases) or core needle biopsy of the lung (1 case); one patient was treated directly after the needle biopsy had been unsuccessful because he needed rapid therapy. In 77/82 (93%) patients it was possible to assess the specific histotype. There was no operative mortality; all the biopsies were performed on an outpatient basis., Interpretation and Conclusions: Our data indicate that core needle biopsy should be considered as an effective and safe procedure in the diagnosis of patients with mediastinal lymphoma with the possibility of determining the tumor subtype and subsequent specific treatment.

Background and Objective: Therapy of both Hodgkin's disease (HD) and aggressive non-Hodgkin's lymphoma (NHL) with mediastinal presentation at the time of diagnosis is frequently followed by radiological detection of residual masses. Computed tomography (CT) scanning is generally unable to detect the differences between tumor tissue and fibrosis. Gallium-67-citrate single photon emission ((67)GaSPECT) can potentially differentiate residual active tumor tissue from fibrosis., Design and Methods: Seventy-five patients with HD or aggressive NHL presenting mediastinal involvement (64% with a bulky mass) were studied with CT and (67)GaSPECT at the end of combined modality therapy (chemo- and radiation therapy)., Results: After treatment, 3/3 (100%) patients with positive (67)GaSPECT and negative CT scan relapsed while only 1/18 (6%) patients with both negative (67)GaSPECT and CT scan did so. At the same time, 54 patients had a positive restaging CT scan (abnormal mass < 10% of size of initial mass). Of these patients, 13 had a positive (67)GaSPECT, 10 of whom (77%) relapsed; 41 had a negative (67)GaSPECT of whom 5 (12%) relapsed. The 4-year actuarial relapse-free survival rate was 90% for those with negative scans compared with 23% for gallium-positive patients (p < 0.000000)., Interpretation and Conclusions: In lymphoma patients with mediastinal involvement, (67)GaSPECT should be considered, at least in patients who are CT positive, the imaging technique of choice for monitoring and differentiating the nature of any residual masses.

Background and Objective: It has been widely demonstrated that one single 7-day course continuous infusion (c.i.) 2-chlorodeoxyadenosine (2-CdA) at a dose of 0.1 mg/kg daily is dramatically effective in inducing high and prolonged complete remission (CR) rates in patients with hairy-cell leukemia (HCL). However, 2-CdA administration often results in severe neutropenia and lymphocytopenia both responsible for the infectious complications observed in these patients. We previously reported preliminary data regarding the effectiveness and toxicity of a modified protocol of 2-CdA administration (0.15 mg/kg 2 hours infusion once a week for 6 courses) in 25 HCL patients. This treatment schedule produced a similar overall response rate compared to standard 2-CdA regimen and appeared to be followed by a lower incidence of infectious episodes. In the present study we report response rate and toxicity of weekly 2CdA administration in a larger cohort of patients and with a longer follow-up., Design and Methods: In a group of HCL patients with a pronounced decrease in neutrophils count (< 1 x 10(9)/L), we modified the standard protocol (0.1 mg/kg daily x 7 days c.i.) by administering 2-CdA at a dose of 0.15 mg/kg 2 hours infusion once a week for 6 courses. Thirty HCL patients, 24 males and 6 females with a median age of 56 years (range 37-76), entered into this protocol. Seventeen out of 30 patients were at diagnosis while the remaining 13 had been previously treated with alpha-interferon (alpha-IFN) (7), or 2-CdA (4) or deoxycoformycin (DCF) (2)., Results: Overall, 22/30 (73%) patients achieved CR and 8 (27%) partial remission (PR) with a median duration of response at the time of writing of 35 months, ranging from 6 to 58 months. Five patients (1 CR and 4 PR) have so far progressed. The treatment was very well tolerated. Five out of 30 patients (16%) developed severe neutropenia (neutrophils < 0.5 x 10(9)/L) and only in two of them we did register an infectious complication which required treatment with systemic antibiotics and granulocyte colony-stimulating factor (G-CSF)., Interpretation and Conclusions: In conclusion, we confirm that weekly administration of 2-CdA at a dose of 0.15 mg/kg for 6 courses appears to be very effective in HCL inducing a high CR rate, similar to that observed with daily c.i. administration. CR durability and relapse/progression rates are also comparable to standard 2-CdA schedule. Moreover this new regimen seems to be safer in pancytopenic patients, markedly reducing life-threatening infectious complications.

Background and Objective: With the development and refinement of new guidance methods for percutaneous biopsies, many investigators have reported studies supporting a role for radiologically guided core-needle biopsy in the diagnosis of malignant lymphoma under certain clinical circumstances. The aims of this report are to evaluate the efficacy of findings at ultrasound (US)-guided core-needle biopsy of abdominal lymphoma on patient care and define the key determinants of clinical success., Design and Methods: US-guided core needle biopsies were performed in 55 patients with abdominal lymphoma: 44 non-Hodgkin's lymphoma (NHL) and 11 Hodgkin's disease (HD); 41 had had no prior lymphoma and 14 had previously diagnosed lymphoma. All the biopsies were performed under US control using a 21-gauge modified Menghini needle. Overall, 53/55 (96%) patients were treated on the basis of biopsy findings only, including 14/14 (100%) patients with a history of lymphoma and 39/41 (93%) patients with no such history., Results: In 46/53 (87%) patients it was possible to assess the specific histotype. No differences between the diagnostic rates of HD and high grade-NHL were recorded. There were no complications related to the biopsies., Interpretation and Conclusions: Our data indicate that abdominal US-guided core-needle biopsy should be considered as an effective and safe procedure in the diagnosis of patients with lymphoma offering the possibility of determining the tumor subtype and the subsequent specific treatment.

Background and Objective: In general, low-grade non-Hodgkin's lymphomas are characterized by a low to moderate proliferative activity and a long clinical course with median survival times ranging from approximately 3 years to 5-8 years. We reviewed data of 209 low-grade non-Hodgkin's lymphoma entered in our institute in 1975 to 1986 to assess their survival., Design and Methods: Treatment was given according to disease stage and current protocols. Thirty patients were treated with radiation therapy, 21 patients with a single alkylating agent, 145 patients with polychemotherapy, and 13 patients were included in the watchful waiting conservative approach., Results: With a median follow-up of 13 years, the actuarial overall survival rates at 5, 10, and 15 years were 60%, 38%, and 27%, respectively. The relapse-free survival was 66% at 5 years, 57% at 10 years, and 45% at 15 years. Concerning the 38 continuous complete responders, 21 were stage I-II and 17 were patients in advanced stage (III-IV)., Interpretation and Conclusions: Therapy of low-grade lymphomas depends mainly on the extent of the disease. Advanced stage disease is often considered incurable. The possibility to obtain a little percentage of complete response must provide considerations in the search for new therapeutic strategies.

The majority of responses produced in patients with low-grade lymphomas are unique among non-Hodgkin's lymphomas (NHL), and even with a more intensive chemotherapy regimen, they are only partial; the very few complete responses which are induced are usually of short duration and do not influence overall survival. There is, therefore, a need for new approaches to the management of low-grade NHLs. Studies are currently in progress to assess the potential benefits in the treatment of NHL offered by new drugs, including fludarabine, idarubicin and 2-chlorodeoxyadenosine. In order to evaluate idarubicin in combination with purine analogs, we used a combination of fludarabine and idarubicin, called the FLU-ID regimen, to treat 10 patients with recurrent low-grade NHL. Of the 10 patients, 2 (20%) achieved complete response, 5 (50%) partial response, and the remaining 3 showed no benefit from the treatment. The 2 CR patients are still in remission after 12 and 14 months, respectively. The median duration of overall survival of all patients was 18 months. These results indicate the efficacy of the FLU-ID regimen in inducing a good remission rate with moderate side effects in recurrent low-grade NHL. On the basis of this pilot study, we planned a cooperative randomized trial for untreated patients.

Background and Objective: Lymphomas of the gastrointestinal tract are the most common type of primary extranodal lymphomas, accounting for 5 to 10% of all non-Hodgkin's lymphomas. In particular, primary intestinal lymphomas represent about 15-20% of gastrointestinal lymphomas. New multimodal therapeutic approaches have improved the prognosis of this once deadly disease: we report a retrospective analysis of our experience with 32 cases of primary western intestinal lymphomas, presenting clinical, therapeutical and prognostic data., Patients and Methods: From March 1989 to November 1995, 32 patients with untreated primary western intestinal lymphomas were submitted to radical surgery plus polychemotherapy (early stages, I and II; 22 patients), or polychemotherapy alone (advanced stage, III and IV; 10 patients). The most frequent symptoms were abdominal pain, nausea, vomiting and weight loss. The tumor was located in the jejunum in 2 cases (6.2%), in the proximal small bowel in 15 cases (46.9%), in the distal and terminal ileum in 8 cases (25%), in the colon and rectum in 4 cases (12.5%), and multiple sites were found in 3 cases (9.4%). According to histology, 26 patients had high-grade and 6 low-grade non-Hodgkin's lymphoma., Results: Stage I-II patients underwent radical resection of the tumor and chemotherapy; advanced (III-IV) stage patients were treated with chemotherapy alone as first-line approach. Of the 32 patients, 24 (75%) achieved a complete response (CR); according to stage, all stage I-II patients had CR, while only 2 of the 10 stage III-IV patients reached CR. The risk of a lower response rate was significantly correlated with the presence of advanced stage (III-IV) (p = 0.000001). The overall 5-year survival rate was 59%, with a relapse-free survival rate of 72% among the 24 complete responders., Interpretation and Conclusions: Intestinal lymphomas differ significantly from their gastric counterpart, not only in pathology, but also with regard to clinical features, management and prognosis. Our experience confirm the efficacy of the surgery-chemotherapy combination in obtaining a good remission rate for localized early primary intestinal lymphoma and indicates that this combination represents the only means for managing complications.

Background and Objective: In the 1980s alpha-interferon (alpha-IFN) dramatically improved the management of hairy cell leukemia (HCL), producing normalization of hematologic parameters including the disappearance of circulating hairy cells in the majority of treated patients, within 6 months. The quality and durability of the response depended on the duration of alpha-IFN treatment; progression of the disease consistently followed discontinuation of alpha-IFN. In this report, we examine the characteristics of long-term responders from our series of 44 HCL patients treated with alpha-IFN., Methods: We report follow-up data on 44 HCL patients who underwent alpha-IFN as first-line treatment between 1985 and 1990. The alpha-IFN dose was 3 x 10(6) U daily for 12-15 months, with 20 patients continuing to receive the same dose three times a week as maintenance treatment for an additional 6-12 months. Of the 44 patients, 8 achieved a CR, 28 a PR and 8 a MR, with an overall response rate of 82%. Thirty-eight (86%) of these patients showed disease progression and were retreated with alpha-IFN (2 pts), 2-chlorodeoxyadenosine (35 pts), or pentostatin (1 pt). So far, all 38 patients are alive and in good unmaintained second response, except for two patients who developed a second neoplasm., Results: Six of the 8 first complete responders are alive and have not required further treatment after completing alpha-IFN. These long responders most often (5/6) presented a hairy cell index (HCI) < 0.50 at diagnosis; all 6 registered a significant reduction in bone marrow infiltration (HCI < 0.10) after induction therapy and underwent alpha-IFN maintenance treatment. These three parameters turned out to be statistically significant when the long-term responders were compared with the failure patients subset (p = 0.003 for HCI at diagnosis; p = 0.001 for HCI at the end of the induction phase; p = 0.003 for the maintenance phase). The median progression-free survival of these 6 long-term responders was 75 months (range, 62 to 78)., Interpretation and Conclusions: Overall, alpha-IFN represents an excellent palliative treatment for most HCL patients. A small subset of these patients could become long-term responders following first-line alpha-IFN therapy alone.

Fludarabine (FLU) is a new antimetabolite chemotherapeutic agent with promising activity in lymphoproliferative disorders and, in particular, in low-grade non-Hodgkin's lymphoma (LG-NHL). Recently, a few reports have described interesting results using FLU in polychemotherapy regimens. In order to evaluate FLU in combination with other antineoplastic agents, we used a combination of FLU and idarubicin, called the FLU-ID regimen, to treat 10 patients with recurrent LG-NHL. The FLU-ID regimen was as follows: FLU 25 mg/sqm i.v. on days 1 to 3 and idarubicin 12 mg/sqm i.v. on day 1. Of the 10 patients, 2 (20%) achieved complete response (CR), 5 (50%) partial response, and the remaining 3 showed no benefit from the treatment. The 2 CR patients are still in remission after 6 and 8 months, respectively. The median duration of overall survival of all patients was 8 months. The major toxic effects observed were neutropenia (40%) and infections and/or febrile episodes (15%); no fatalities due to drug side effects occurred. These results indicate the efficacy of the FLU-ID regimen in inducing a good remission rate with moderate side effects in recurrent LG-NHL.

Background: During the last 20 years Hodgkin's disease (HD) has become one of the most curable neoplasms; in fact, more than 75-80% of patients are expected to achieve long-term relapse-free survival with appropriate therapy. However, overall survival has been affected by intercurrent or treatment-induced diseases such as the increased risk of cardiac toxicity in patients who received mediastinal irradiation., Methods: The incidence of cardiac abnormalities after mediastinal radiotherapy was assessed in 102 consecutive HD patients who underwent this treatment from January 1970 to December 1980. Basal investigation procedures included electrocardiogram and echocardiography; myocardial perfusion scintigraphy with 201-thallium and coronary arteriography were performed in selected patients., Results: Eleven patients (10.8%) presented cardiac abnormalities, which were asymptomatic in three cases. Eight cases of myocardial ischemia and 3 of constrictive pericarditis were observed. The incidence of late cardiotoxic effects was related to total mediastinal dose and to the irradiation technique., Conclusions: The increasing duration of follow-up shows that as mediastinal irradiation increases so does the risk of late cardiotoxic side effects. For this reason, a proper treatment strategy should reduce these risk factors through new combined modality protocols and routine evaluation of cardiologic follow-up.

Extended field radiation therapy represents the main therapeutic option in early stage Hodgkin's disease with favorable prognostic features. Its role however has recently been criticized, mainly due to the high incidence of late complications in irradiated tissues. Furthermore, surgical staging, which in the opinion of many is mandatory for proper selection of patients for radiotherapy alone, has a well-known morbidity, and splenectomy has been associated with a high risk of secondary leukemias. Lastly, the failure rate after radiotherapy only is not negligible and second-line treatment is not always successful. A review of our experience and of the recent literature has allowed us to refute these objections. The results of radiotherapy, when properly performed, are highly reliable and have been reproducible in many Institutions. Chemotherapy alone cannot yet be regarded as an alternative to radiotherapy in these patients since data reported on this issue are conflicting. Present knowledge regarding the relationship between clinical features and the risk of occult subdiaphragmatic spread allows patients with localized disease to be selected without surgical staging; the results of radiotherapy in clinically staged patients confirm this statement. Concern for the late effects in irradiated tissues is justified, and future efforts should be directed at reducing the toxicity of this treatment. Associating a short chemotherapy course with low-dose radiotherapy to involved sites could help to achieve this goal.

Background: A fundamental principle in the therapeutic strategy for recurrent lymphomas is the employment of agents that are not part of the usual front line combination regimens. Ideally, the cytotoxic agents should lack complete cross resistance with those utilized up front., Patients and Methods: A three-drug combination of ifosfamide, epirubicin and etoposide (IEV) was used to treat 20 patients with relapsing or refractory high-grade non-Hodgkin's lymphoma (HG-NHL) or Hodgkin's disease (HD)., Results: Of 14 patients with HG-NHL, 5 (36%) achieved a complete response (CR) and 4 partial remission (PR), giving an overall response rate of 64%. To date, all the complete responders are still in CR at +5, +5, +6, +7, and +9 months, respectively. Of 6 patients with HD, 4 (66%) obtained CR and 2 PR, giving an overall response rate of 100%. The 4 CRs are still in remission after +4, +5, +9, and +13 months, respectively. Clinical and hematologic toxic effects were moderate: neutropenia was responsible for delaying treatment for a week in 6 patients., Conclusions: These results confirm the efficacy of the IEV regimen in inducing a good remission rate with moderate side effects in relapsing/refractory HG-NHL and HD patients and they show that further investigations with this combination are warranted.

Background: Fludarabine (FLU) is a fluorinated purine analogue with antineoplastic activity in lymphoproliferative malignancies. Recently, some in vitro reports have showed the effective role of FLU on the activation of apoptosis., Materials and Methods: The induction of programmed cell death (apoptosis) by fludarabine (FLU), an adenine nucleoside analogue, alpha-interferon (alpha-IFN), and FLU plus alpha-IFN was evaluated in vitro against freshly isolated, chronic-phase Ph1+ chronic myeloid leukemia (CML). Apoptosis was detected by electrophoresis gel of DNA oligonucleosomal fragments in 8 CML samples., Results: Only FLU and FLU plus alpha-IFN significantly activated apoptosis in all the samples, suggesting selective activity on CML cells. On the other hand, alpha-IFN alone did not activate programmed cell death., Conclusions: Our data show apoptotic activity for FLU on CML cells. Programmed cell death may be suppressed in cells carrying the bcr-abl transcript, and FLU might remove this resistance in the neoplastic cell cycle. This preliminary report justifies using FLU in pilot clinical trials for chronic phase Ph1+ CML patients.

Background: Fludarabine monophosphate (FLU) is an adenine nucleoside analogue with promising therapeutic activity in lymphoproliferative disorders. In addition, the effectiveness of alpha-interferon (alpha-IFN) in low-grade non-Hodgkin's lymphoma (LG-NHL) and B-cell chronic lymphocytic leukemia (B-CLL) has been demonstrated in several clinical trials., Methods: In a phase II study of 45 patients with B-CLL and 28 with LG-NHL, we used FLU as second and third-line chemotherapy. Dosages of 25 mg/m2 were given in 30-minute infusions for 5 consecutive days. Treatment was repeated every 28 days depending on patients' clinical status for a maximum of 6 cycles. Entrance in the human lymphoblastoid alpha-IFN maintenance portion of the study depended on response to initial FLU. Following randomization we administered alpha-IFN, or no therapy at all, to patients who obtained a complete or a partial response after FLU therapy. The alpha-IFN dose was 3 x 10(6) U three times per week until disease progression., Results: Twenty-one B-CLL patients achieved major responses, as did 17 of those with LG-NHL. Twenty-four of the former group and 11 of the latter failed to respond or obtained only a minor response. The 38 patients who responded well and entered the second part of the trial showed significant prolongation of remission duration with maintenance alpha-IFN., Conclusions: In consideration of its significant activity, the role of FLU in the management of lymphoproliferative disorders needs to be evaluated further; at the same time, this preliminary analysis seems to indicate that maintenance alpha-IFN may extend remission duration in B-CLL and LG-NHL.

Background: Age is an important factor, especially in patients with advanced lymphoma who require more intensive and extensive therapy for any possible chance of cure. In fact, attenuation of treatment to diminish treatment-related toxicity decreases the capacity of the therapy to effect a cure., Methods: Between December, 1991 and February 1993, 29 previously untreated patients 60 years and older with high-grade non-Hodgkin's lymphoma (HG-NHL), according to the Kiel classification, were treated with a combination therapy including cyclophosphamide, mitoxantrone, vincristine, etoposide, bleomycin, and prednisone (VNCOP-B)., Results: Twenty-two patients achieved a complete pathologic remission and 5 had a partial response, with a reduction of more than 50% of tumor-related manifestations. Only two cases were resistant to VNCOP-B. Overall survival was 75%, with a median follow-up of 13 months from diagnosis; four of the patients who achieved complete response relapsed after a median follow-up of 11 months from the completion of treatment. Clinical and hematologic toxicity was irrelevant: in 12 patients, neutropenia was responsible for a temporary interruption of therapy for 1-2 weeks., Conclusions: This regimen was effective in inducing a good remission rate with moderate toxic effects in elderly patients with HG-NHL, but a longer follow-up is warranted before definitive conclusions can be drawn.

Background: Granulocyte colony stimulating factor (G-CSF) safely stimulates the production of neutrophils in normal people and neutropenic patients. Phase II studies have been completed that explored the role of G-CSF in either abrogating or accelerating recovery from chemotherapy-induced neutropenia., Methods: Fourteen patients with resistant/relapsed high-grade non-Hodgkin's lymphoma were treated with a dexamethasone, cytarabine and cisplatin (DHAP) regimen, and with G-CSF between chemotherapeutic courses., Results: All patients showed a rise in neutrophil count; none was neutropenic when hospitalized for subsequent DHAP courses. Furthermore, the interval between cycles was decreased in 11 of the 14 patients. The overall response rate was 86%, with 4 patients obtaining complete remission., Conclusions: Administration of G-CSF was associated with an acceleration of neutrophil recovery, indicating its potential to reduce the risk of infection and to maintain planned chemotherapy doses.

Background: A retrospective analysis on HODGKIN'S DISEASE (HD) was finalized to see if changing the management and therapy during the years we improved the cure rate of lymphomas and reduced the incidence of side effects due to therapy. Up to twenty years' experience was based in two major therapeutic periods: the first included patients observed between 1970 and June 1980 and the second between July 1980 and December 1987. Significant differences between the two periods were the reduction of splenectomies as staging procedure, the reduction of radiation dose and extension and the sequential use of MOPP/ABVD instead of MOPP alone., Methods: The analysis included all patients observed over the twenty years under study by looking to the differences concerning response to therapy, survival, relapse-free survival and major consequences due to therapy, namely death not directly related to lymphoma. 377 pts entered the first period and 193 the second one with a minimum follow-up of 4 years., Results: Significant differences were recorded on CR rate, 80.9% vs 90.5%, respectively (p = 0.0024) and deaths in CR, 15.1% vs 2.6%, respectively (p = 0.000). The overall survival shows a probability of 60% and 83% at 11 years for the first and the second group, respectively (p = 0.000) being the probability of survival of 50% at 20 years for the first group of pts. The probability of being in remission is similarly of 79% and 78%, for the first and second group, respectively. The risk of death in remission accounting all causes not related to lymphoma shows a 17% probability vs 6% at 11 years (p = 0.006) for the first and second group, respectively, being 38% for the former group at 20 years. The most frequent single cause of death in remission was secondary leukemia which was recorded in 14 pts on the group of pts observed between 1970 and 1980, all splenectomized and treated by MOPP and extensive radiotherapy., Conclusions: The modifications of therapy of HD have produced improvements concerning the prognosis of pts; these improvements are due mainly to the reduction of late side effects such as acute leukemia and second solid tumor, and to the increase of remission rate and cure rate of the lymphoma.

In the past several decades, scientific and therapeutic advances have transformed Hodgkin's disease from a uniformly fatal illness to one that can be treated with the expectation of long-term remission or cure in the majority of cases. Because patients now survive for long periods after treatment, various late complications are being identified. Among patients with such late complications, some have been reported to experience "very late" relapses (> 10 years). Here we document recurrences in three patients with Hodgkin's disease more than 10 years after remission.

Background: Following irradiation alone, secondary acute leukemia is extremely uncommon; following chemotherapy alone, the risk is increased, but not as much as when continued maintenance chemotherapy or combined modality treatments are used., Patients: The risk of secondary acute nonlymphocytic leukemia (ANLL) was assessed in 552 patients with Hodgkin's disease (HD), who were diagnosed at the Hematology Institute of Bologna from 1970 through 1984 and followed-up through July, 1990. Median follow-up time was 12 years., Results: ANLL developed in 14 of 328 patients treated with the combined modality of extended-field radiotherapy (RT) plus chemotherapy (CT). All ANLL was observed in patients who had received the mechlorethamine-vincristine-procarbazione-prednisone (MOPP) regimen. No ANLL was documented among 115 patients treated with RT alone, nor among the 109 given CT alone. Leukemia, which developed 34-184 months after diagnosis of HD, was always preceded by a preleukemic phase and was fatal (after 1-12 months) to 13 patients. The karyotype of the leukemia cells was studied in 11 of the 14 patients and was always abnormal., Conclusions: A Cox's Linear Logistic Model that was performed did not demonstrate that the treatment categories, age, sex, and splenectomy were prognostic factors. Because all ANLL was observed in patients who were treated with extended-field RT plus MOPP and who had undergone splenectomies at diagnosis of HD, further research with larger numbers of patients and longer follow-up should be pursued. Thus with such additional data, clinicians could come to appreciate fully the statistical significance of our interesting observations.

In this review of current therapy for mycosis fungoides, the analytical data have been extrapolated from the literature. We have considered the various therapeutic modalities such as topical therapy, photochemotherapy, electron beam radiation therapy, systemic chemotherapy, the combined modalities, as well as the use of interferon and other alternative biological approaches. We conclude with a final section on comments and recommendations that may prove useful in the design of appropriate therapeutic strategies.