Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab.

Rituximab is a chimeric anti CD-20 monoclonal antibody containing human IgG1 kappa constant regions, with murine variable regions. The anti-lymphoma effects of Rituximab are probably due to complement and antibody-dependent cell-mediated cytotoxicity, and induction of apoptosis. Phase II trials have demonstrated a strong activity of rituximab alone in indolent B non-Hodgkin lymphoma, especially in patients with follicular lymphoma. The most utilized dose-schedule is 375 mg/m(2) weekly x 4. The association with chemotherapy or with interferon-alpha increases Rituximab efficacy. More recently, Rituximab have showed activity also in diffuse large cell lymphoma, mantle cell lymphoma and in other B-malignancies. Good results have also been obtained utilizing Rituximab for in vivo purging. However, we are still far from having found a definite position for Rituximab in the treatment of lymphoproliferative disorders. The aim of future studies should be to develop new strategies that will hopefully produce the most effective Rituximab-based regimens in order to find the Rituximab key position in the treatment of B-malignancies

The role of surgery in the treatment of gastrointestinal lymphomas other than low-grade MALT lymphomas.

BACKGROUND AND OBJECTIVE: A bias in clinical investigations on gastrointestinal lymphomas is the lack of testing the intention to treat as to resection, emergency conditions at presentation and selection brought about by the evaluation of feasibility of surgery. DESIGN AND METHODS: A prospective study involved 154 patients with gastrointestinal nodular or high-grade MALT lymphomas, 111 with a gastric and 43 with an intestinal presentation. The decision to resect or treat conservatively was left to clinicians, on condition that it was previously defined for each patient. RESULTS: Failure-free survival was significantly higher in the 106 resected patients than in the 48 unresected ones but did not differ according to either primary intention to treat or emergency surgery/elective treatment. Survival was similar in patients operated on by choice and in those because of an emergency. Intentionally unresected patients had a significantly better survival than those not undergoing surgery despite the initial intention, for a number of clinical reasons. Patients with gastric lymphoma survived longer than those with intestinal disease and prognostic factors were analyzed separately in the two groups. The best predictors of prognosis were performance status and serum lactic dehydrogenase level in gastric lymphomas, resection alone in intestinal ones. INTERPRETATION AND CONCLUSIONS: The prognosis of gastric lymphomas depends on lymphoma-related factors and not on surgical treatment. The prognosis of intestinal ones is exclusively related to surgery. These data support the appropriateness of different clinical approaches to gastric and intestinal lymphomas.

Validation of the international prognostic index in working formulation group A low-grade non-Hodgkin's lymphoma: retrospective analysis of 137 patients from the Gruppo Italiano per lo Studio dei Linfomi registry.

BACKGROUND AND OBJECTIVE: The subset of non-follicular non-Hodgkin's lymphoma (NHL) includes patients with varied prognoses, thus suitable for different therapeutic approaches. The International Prognostic Index (IPI), originally proposed for aggressive NHL, has been demonstrated to be of prognostic relevance also in follicular NHL. The main aim of the study was to validate the IPI in this histologic category; in addition, the specific prognostic classification, currently employed in the Gruppo Italiano per lo Studio dei Linfomi (GISL) prospective therapeutic trials and based on different features, more similar to those applied to chronic lymphocytic leukemia, was analyzed. DESIGN AND METHODS: The present series consists of 137 evaluable patients affected by Working Formulation group A NHL out of 256 cases referred to the GISL Registry. The retrospective prognostic study included the evaluation by both univariate and multivariate analyses of overall survival, response to therapy and response duration. The IPI was applied as originally proposed. The GISL definition of indolent and aggressive disease at diagnosis was based on the presence of B symptoms, bulky disease, anemia and thrombocytopenia. RESULTS: The distribution of patients in IPI risk groups was rather unbalanced with 18%, 47%, 28% and 7% of cases classified as low (L), intermediate-low (IL), intermediate-high (IH) and high (H) risk, respectively. The median overall survival was not reached in either L or IL risk groups, and was 84.1 and 7.4 months for IH and H risk groups, respectively (p=0. 0005). A simplified IPI model was designed merging patients in both intermediate risk groups and the statistical difference of survival retained its significance. GISL prognostic stratification was demonstrated to have a significant association with survival, with a median survival of 71.3 months in aggressive disease and a median survival not reached at 152 months in indolent disease. Both the simplified IPI model and the GISL risk definition retained their significance in multivariate analysis for overall survival, while for response to therapy only the simplified IPI model resulted to be of statistical significance. In addition, the GISL prognostic stratification identified patients with different outcomes within the IPI intermediate risk group, with a median survival of 70.2 months for patients with aggressive disease wheras the median survival for those with indolent disease was not reached. Finally, a prognostic score resulting from the integration of the simplified IPI and the GISL system was statistically validated. INTERPRETATION AND CONCLUSIONS: The retrospective analysis of this series demonstrates the validity of the IPI in non-follicular indolent NHL and the usefulness of integrating the IPI parameters with disease specific prognostic variables.

Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi.

Patients (n-987) with a histologically confirmed diagnosis of follicular lymphoma were studied with the aim of developing a prognostic model specifically devised for this type of lymphoma. We collected information on age, sex, Ann Arbor stage, number of extranodal disease sites, bone marrow (BM) involvement, bulky disease, B symptom criteria (fever, night sweats, and weight loss), performance status (PS), serum lactate dehydrogenase (LDH) level, serum albumin level, hemoglobin level, and erythrocyte sedimentation rate (ESR). In the training sample of 429 patients with complete data, multivariate analysis showed that age, sex, number of extranodal sites, B symptoms, serum LDH level, and ESR were factors predictive for overall survival. Using these 6 variables, a prognostic model was devised to identify 3 groups at different risk. The 5- and 10-year survival rate was 90% and 65% for patients at low risk, respectively; 75% and 54% for patients at intermediate risk; and 38% and 11% for those at high risk (log-rank test, 86.62; P <. 0001). The model was also predictive (P =.0001) in the validation sample of 265 patients with complete data only for the 6 variables used in the development of the model and even in the group of 210 patients from the validation sample uniformly treated with doxorubicin-containing regimens (P =.0001). The prognostic model appears to be very useful in identifying patients with follicular lymphoma at low, intermediate, or high risk.

[Celiac disease and lymphoma]. / Malattia celiaca e linfoma.

Celiac disease (CD) has been acknowledge as being responsible for numerous secondary pathologies, in particular autoimmune and neoplastic diseases. Whether CD is more prevalent in patients with non-Hodgkin's lymphoma (NHL) than in the normal population is not known. Accordingly, we carried out a study of 86 patients hospitalized in the Section of Oncology, Haematology and Internal Medicine of the Department of Medical, Oncological and Radiological Sciences of the University of Modena and Reggio Emilia and who, between 1988 and 1995 had been diagnosed as affected by NHL. On diagnosis, and before the beginning of antitumour therapy, all the patients were tested for antigliadin (AGA IgA and IgG) and antiendomysium (EMA) antibodies together with total class IgA antibody levels. Our findings showed that none of the 86 patients had an IgA deficit, while one tested positive for AGA IgA (43.9% v.n. < 7.5). The same patient also tested positive for EMA. The extremely high sensitivity and specificity of the AGA IgA and EMA led us to conclude that the patient was affected by CD, although his early death precluded confirmation by biopsy. The presence of one celiac patient among 86 NHL patients examined at the onset of the disease would suggest that CD is not infrequent in NHL. The numbers involved in our study are insufficient for statistical purposes, and we are therefore awaiting the results of a SIGEP multi-centre study into the connection between CD and lymphomas.

Retrospective analysis of mantle cell lymphoma: experience of the "Gruppo Italiano per lo Studio dei Linfomi" (GISL).

BACKGROUND AND OBJECTIVE: Mantle cell lymphoma is a recently recognized histologic entity with specific biological and clinical features. Clinically, the reported unfavorable outcome of these patients has focused attention on this category of non-Hodgkin's lymphoma (NHL). DESIGN AND METHODS: The slide specimens of 69 NHL patients, originally classified as Working Formulation (WF) group B and E, were reviewed. The clinical features at presentation, response to therapy, response duration and survival were analyzed in cases reclassified as MCL. The correlation between clinical and histologic characteristics and the final outcome was evaluated. RESULTS: Out of 69 cases, 34 specimens were reclassified as MCL; in 6 patients, previously classified as WF group B, the nodular pattern was confirmed; in 2 instances the blastoid form was recognized. After a median follow-up of 35.7 months, the entire series displayed a median overall survival of 41.2 months; a significantly longer survival was associated with the nodular histologic pattern, IPI score < 2, response achievement, and a higher Hb level. The vast majority of patients received anthracycline-containing combination chemotherapy. Complete remission rate was 38.8% and overall response rate was 67.6%; response achievement was significantly influenced only by Hb level. Median response duration was 23.3 months. INTERPRETATION AND CONCLUSIONS: The present study confirms the unfavorable clinical course of MCL and the possible need for an alternative therapeutic strategy for this NHL category. Therefore, the correct identification of MCL at diagnosis appears of relevance.

Efficacy of two different ProMACE-CytaBOM derived regimens in advanced aggressive non-Hodgkin's lymphoma. Final report of a multicenter trial conducted by GISL.

BACKGROUND AND OBJECTIVE: To compare the efficacy of ProME(Epidoxorubicin)CE-CytaBOM (PE-C) and ProMI(Idarubicin)CE-CytaBOM (PI-C) in the treatment of adult patients with aggressive non Hodgkin's lymphoma in a multicenter randomized controlled trial performed by 18 centers of the Italian Lymphoma Study Group (GISL). DESIGN AND METHODS: One hundred and twenty-eight and 122 patients were randomly assigned to receive either 6 courses of PE-C or PI-C, respectively. Some patients achieving complete remission with induction therapy participated in another randomized study comparing no further therapy versus maintenance therapy consisting of four blocks of two drugs. RESULTS: The rate of CRs was 62% and 64% for patients treated with PE-C and PI-C, respectively (p = 0.51). The 5-year relapse-free survival was 60% for PE-C and 53% for PI-C (p = 0.29). The estimated relapse-free disease survival rates at 4 years were 75% for patients in the consolidation group and 57% for those in the observation group (p = 0.11). Patients alive in first complete remission 4 years after study entry were estimated to be 39% in the PE-C arm and 38% in the PI-C arm (p = 0.90). The 3-year and 5-year estimated survival rates were 61% and 55% for the PE-C group and 56% and 47% for the PI-C group (p = 0.26). Fatal toxicities occurred in 7 patients (2.9%) with active disease and in 4 patients (1.7%) in complete remission. Stage (p = 0.04), bulky disease (p = 0.02), serum LDH (p = 0.0006), serum albumin (p = 0.0051), hemoglobin (p = 0.0011), performance status (p = 0.0001), International prognostic index (p < 0.0001) and the index proposed by the French group G.E.L.A. (p < 0.0001) were of prognostic value. In a multivariate analysis (Cox regression model) alternatively IPI alone or G.E.L.A. index plus performance status emerged as independent prognostic factors. INTERPRETATION AND CONCLUSIONS: The present study indicates that epirubicin and idarubicin in a combined chemotherapy regimen, have similar activities. The toxic profile also indicates the safety of both anthracyclines at the dosages employed, suggesting their possible dose escalation in a combined chemotherapy setting. PE-C and PI-C were both effective and feasible regimens in an outpatient setting, with acceptable cardiovascular toxicity. The trend toward a better outcome in patients undergoing consolidation therapy after the achievement of a complete remission, warrants further investigation.

High-dose therapy autologous stem cell transplantation vs conventional therapy for patients with advanced Hodgkin's disease responding to first-line therapy: analysis of clinical characteristics of 51 patients enrolled in the HD01 protocol. EBMT/ANZLG/Intergroup HD01 Trial.

Whether high-dose therapy (HDT) plus autologous stem cell transplantation (ASCT) ought to be included in the initial treatment plan for those patients with unfavourable Hodgkin's disease, a wide cooperative study (HD01 protocol) was approved, comparing HDT followed by ASCT vs conventional chemotherapy (CT). Patients were eligible for the study if they had at least two of the following adverse prognostic factors: high serum LDH levels, mediastinal mass >0.45, more than one extranodal involved site, low hematocrit (<34% for women and <38% for men), and inguinal involvement. Those patients achieving complete or partial remission with four courses of ABVD or ABVD-containing chemotherapy were randomized to receive either HDT plus ASCT or four additional courses of chemotherapy, followed by ASCT in second remission, if appropriate. Between April 1993 and September 1995, 55 patients from 14 different centers have been enrolled into the trial. Twenty patients (45%) were in stage IV, and 37 patients (84%) had systemic symptoms. Twenty-seven patients (61%) had two adverse prognostic factors, and 17 patients (39%) had three or more risk factors. After four cycles of ABVD-containing CT, 44 patients were assessable for response. Overall 12 patients achieved CR (27%), 25 obtained a PR (57%) and seven patients failed to respond (16%). Thirty-six patients were randomized between ASCT (20 patients) or four additional cycles of conventional CT (16 patients). With a median follow-up after ASCT of 13 months (range 1-23 months), no major ASCT-related toxicity has been reported to the trial office. In conclusion, the first 44 patients registered in the HD01 trial and assessable for response, had a very aggressive disease and responded poorly to conventional CT, thus warranting a more aggressive approach, such as HDT followed by ASCT.

Anaplastic large cell lymphoma (CD30+/Ki-1+). Analysis of 35 cases followed at GISL centres.

Between January 1988 and June 1992, 35 patients with primary anaplastic large cell lymphoma (ALCL)CD30+ were referred to one of the institutions participating in GISL (Gruppo Italiano per lo Studio dei Linformi). 16 patients were treated with ProMACE-CytaBOM, two with MACOP-B, one with CHOP and one with LSA2-L2. As of November 1990, all newly diagnosed patients were treated with MOPP/EBV/CAD hybrid. 27 (77%) cases of ALCL CD30+ and 8 (23%) cases of Hodgkin's-related (HR) lymphoma CD30+ were diagnosed. Extranodal disease was present in 22 cases (63%), and 8 patients (23%) had primary bone marrow involvement. Twenty-three complete remissions (CR) (66%), six partial remissions (PR) (17%) and six no remissions (NR) (17%) were achieved with induction therapy. Results achieved with ProMACE-CytaBOM and MOPP/EBV/CAD hybrid were comparable. The overall response rate (CR+PR) was 85% for patients with classic ALCL CD30+ and 87% for those with HR lymphoma CD30+. The 3 year estimated overall survival rate was 66% and the 3 year relapse free survival rate was 65% for the entire group. The only significant favourable prognostic factor was the achievement of CR with initial therapy. Our findings suggest that ALCL (CD30+/Ki-1+) has a clinical outcome similar to aggressive non-Hodgkin's lymphoma (NHL). The use of an anthracycline-containing regimen will provide a change of cure in approximately 65% of cases.