Lenalidomide-prednisone induction followed by lenalidomide-melphalan-prednisone consolidation and lenalidomide-prednisone maintenance in newly diagnosed elderly unfit myeloma patients.

This multicenter phase II trial evaluated the safety and efficacy of lenalidomide-prednisone (RP) induction, followed by lenalidomide-melphalan-prednisone (MPR) consolidation and RP maintenance in elderly unfit newly diagnosed myeloma patients. Patients received four 28-day RP induction courses (lenalidomide 25 mg/day on days 1-21 and prednisone 50 mg three times/week), followed by six 28-day MPR consolidation cycles (melphalan 2 mg, prednisone 50 mg three times/week and lenalidomide 10-15 mg/day on days 1-21), and maintenance with lenalidomide (10 mg/day on days 1-21 every 28 days) plus prednisone (25 mg three times/week). Forty-six patients were enrolled. Median age was 75 years, 59% of patients had at least one comorbidity and 35% at least two. Partial response rate was 80%, including 29% very good partial response. Median time to progression was 19.6 months, median progression-free survival was 18.4 months and 2-year overall survival was 80%. At the tolerated consolidation dose (melphalan 25 mg/month and lenalidomide 10 mg/day), the most frequent grade 3 adverse events were neutropenia (36.4%), anemia (12.1%), cutaneous reactions (18.2%) and infections (12.1%). Grade 4 neutropenia occurred in 12.1% of patients. In conclusion, RP induction followed by MPR consolidation and RP maintenance showed a manageable safety profile, and reduced the risk of severe hematological toxicity in unfit elderly myeloma patients.

Long term outcome of localized aggressive non-Hodgkin lymphoma treated with a short weekly chemotherapy regimen (doxorubicin, cyclophosphamide, bleomycin, vincristine, and prednisone) and involved field radiotherapy: result of a Gruppo Italiano Multiregionale per lo Studio dei Linfomi e Leucenie (GIMURELL) study.

Recently, management of limited stage diffuse large cell lymphoma (DLCL) is trending toward a low intensity chemotherapy approach. Since 1993 we have used a brief weekly (6 weeks) chemotherapy scheme (Doxorubicin, Cyclophosphamide, Bleomycin, Vincristine, and Prednisone = ACOP-B) followed by involved field radiotherapy in 207 consecutive patients with well defined localized DLCL without age limit (median 57 years, range 18-85). Treatment was completed as designed in 183 of 207 patients (88%). One hundred and ninety-nine patients (96%) achieved complete remission. At a median follow-up of 66 months 170 patients are alive (82%), 168 of them free of disease. Twenty-nine patients experienced relapse after achieving a complete remission. Kaplan-Meier, risk of relapse was 24% after 13 years. Thirty (14.5%) patients have died, 14 (6.8%) due to lymphoma progression, one due to regimen toxicity and 15 (7.2%) from other causes while remaining in complete remission. The probability of overall survival and event free survival at 13 years was 78% (95% CI 70-87%) and 63% (95% CI 50-75), respectively. Crude rate of secondary malignancy was 5.26 /1000 person-years. The ACOP-B regimen plus involved field radiotherapy is well tolerated both short and long term and is an effective chemotherapy scheme for very well defined limited stage aggressive non-Hodgkin lymphomas in all age categories.

Point mutations of the BCL-6 gene: clinical and prognostic correlation in B-diffuse large cell lymphoma.

Although point mutations of the 5' noncoding regions of the BCL-6 proto-oncogene are frequently detected in B-diffuse large cell lymphoma (B-DLCL), a thorough analysis of the clinical correlation of these mutations has not been performed to date. In this study, BCL-6 mutations were examined by DNA direct sequencing in 103 patients with B-DLCL. BCL-6 mutations were found in 53/103 patients, including 38/76 treated with standard chemotherapy and 15/27 treated with autologous stem cell transplantation (ASCT) up front. The presence of BCL-6 mutations was correlated with clinical features at diagnosis and outcome. Mutated patients had a significantly higher LDH level (66% vs 38%, P < 0.05), and bulky disease (51% vs 32%, P = 0.05). In the whole series of patients BCL-6 mutations did not affect CR and OS. Patients with BCL-6 mutations tended to have a prolonged 5-years DFS and FFS compared to those without mutations (DFS 82% vs 63%, FFS 63% vs 49%). Among B-DLCL treated with standard chemotherapy, mutated patients showed a significantly improved 5-year DFS (85% vs 61%, P < 0.05) and, notably, the only four relapses observed among mutated patients occurred in less than 8 months. The multivariate regression analysis (P < 0.01) with DFS as endpoint confirmed the independent prognostic value of BCL-6 mutations. There was a trend for 5-year failure-free survival to be better for patients with BCL-6 mutations (63% vs 43%, P = 0.09). In the 27 patients treated with ASCT, BCL-6 mutations did not correlate with outcome. These results suggest that BCL-6 mutations may predict a higher chance of being free of disease in B-DLCL treated with standard chemotherapy. Larger series of patients need to be analyzed to evaluate the clinical relevance of BCL-6 mutations properly.

Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia.

BCL-6 mutations are accumulated during B-cell transit through the germinal center (GC) and provide a histogenetic marker for B-cell tumors. On the basis of a comprehensive analysis of 308 B-cell neoplasms, we (1) expand the spectrum of tumors associated with BCL-6 mutations; (2) corroborate the notion that mutations cluster with GC and post-GC B-cell neoplasms; and (3) identify heterogeneous mutation frequency among B-lineage diffuse large cell lymphoma (B-DLCL) subsets. Mutations are virtually absent in acute lymphoblastic leukemia (P <.001) and mantle cell lymphoma (P <.05), whereas they occur frequently in GC or post-GC neoplasms, including lymphoplasmacytoid lymphoma, follicular lymphoma, MALT lymphomas, B-DLCL and Burkitt lymphoma. Among B-DLCL, mutations occur frequently in systemic nodal B-DLCL, primary extranodal B-DLCL, CD5(+) B-DLCL, CD30(+) B-DLCL, and primary splenic B-DLCL, suggesting a similar histogenesis of these B-DLCL subsets. Conversely, mutations are rare in primary mediastinal B-DLCL with sclerosis (10.0%; P <.01), supporting a distinct histogenesis for this lymphoma. Longitudinal follow-up of B-DLCL transformed from follicular lymphoma shows that they BCL-6 mutations may accumulate during histologic progression. Mutations also occur in some B-cell chronic lymphocytic leukemias, small lymphocytic lymphomas, and hairy cell leukemias, consistent with the hypothesis that a fraction of these lymphoproliferations are related to GC-like cells. Finally, the molecular pattern of 193 mutational events reinforces the hypothesis that mutations of BCL-6 and immunoglobulin genes are caused by similar mechanisms. (Blood. 2000;95:651-659)

Rearrangements of bcl-6, bcl-2, c-myc and 6q deletion in B-diffuse large-cell lymphoma: clinical relevance in 71 patients.

BACKGROUND: B-diffuse large-cell lymphomas (DLCL) have been associated with some molecular lesions, but the role of such lesions as prognostic markers is still controversial. This report concerns an investigation of the frequency and clinical correlation of bcl-6, bcl-2, c-myc rearrangements and 6(q) deletions in B-DLCL. PATIENTS AND METHODS: The presence of these genetic lesions was analyzed in samples of lymph nodes or bone marrow collected at diagnosis in 71 patients with B-DLCL, all treated with an anthracycline-containing chemotherapy regimen. RESULTS: Rearrangement of bcl-6 was found in 11 patients (15%), rearranged bcl-2 in 12 (17%), 6(q) deletions in 10 patients (14%) and c-myc rearrangement in four (6%). Patients with rearranged bcl-6 tended to have a more aggressive disease than patients with germ-line bcl-6 (intermediate-high/high risk according to IPI criteria: 73% vs. 43%), but there were no differences in three-year survival rates (62% vs. 42%) between the two groups. The numbers of involved extranodal sites were similar in patients with rearranged and those with germ-line bcl-6. Patients with bcl-2 rearrangement appeared to have a less aggressive disease than those with germ-line bcl-2 (low/ low-intermediate risk 75% vs. 47%) and a slightly better three-year survival rate (70% vs. 41%) but again the difference was not significant. Both groups with or without 6(q) deletion had similar clinical characteristics and outcomes. The four patients with c-myc rearrangement had aggressive disease and did poorly. CONCLUSIONS: The analysis of molecular lesions in B-DLCL may be useful for a better diagnostic definition; however, in this study we were unable to show that the evaluated genetic lesions had a significant impact on clinical outcome.

Mantle cell lymphoma: a retrospective study on 27 patients. Clinical features and natural history.

BACKGROUND AND OBJECTIVE: Mantle cell lymphoma (MCL) is a separate histological and clinical entity recently recognized in the new revised European-American Lymphoma Classification. Little information exists regarding its therapy. We report the results of a retrospective study of 27 patients affected by MCL evaluating the clinical characteristics and the results of different therapeutical options used during the period of observation. DESIGN AND METHODS: From 1983 to 1993, we observed 27 patients affected by MCL according to the criteria proposed by European Lymphoma Task Force in a revision of 55 cases classified as NHL E according to Working Formulation (WF) criteria. We analyzed the clinical characteristics, the prognostic factors and the O.S. of these patients. RESULTS: The clinical characteristics of our patients (pts) are similar to those observed in other series: male prevalence, median age 62 years, B symptoms in 9 cases, P.S. > 2 in 11 cases, 3 pts were in stage I and II, 4 in stage III, 20 in stage IV; 18 pts had a bone marrow involvement, 13 pts had spleen enlargement and 14 had extranodal localization; 8 pts had bulky tumor and 5 had LDH above normal. The CR rate was 51.8%, the median O.S. was 43 months, and DFS was 18 months; the pts without bulky disease and with localized disease had a better CR rate. The inclusion of an anthracycline in the regimen did not affect the results. INTERPRETATION AND CONCLUSIONS: Our results were not divergent from those present in literature. The mantle cell lymphoma is an incurable and highly aggressive disease. Autologous bone marrow transplantation as support of high dose chemotherapy or allogenic bone marrow transplantation may be a chance for some patients, but not for the majority of patients, which are older than 65 years. Studies of a larger series and different therapeutical approaches, i.e. using biological modifiers in association or as maintenance after chemotherapy are essential.

Cell proliferation, bcl-2, c-myc, p53 and apoptosis as indicators of different aggressiveness in small lymphocytic lymphoma (SLL).

Cell proliferation activity, by MIB1 mAb, expression of bcl-2, c-myc and p53 gene proteins and apoptotic index (AI) were assessed in 54 cases of SLL and compared to the morphological subtypes of this disorder, defined by Lennert on the basis of amount and distribution of small and larger activated lymphocytes as diffuse, tumor-forming and pseudofollicular subtypes (DS, TFS, PFS). MIB1 scores showed significant differences between DS, PFS and TFS (5.5%, 16.61% and 24.14%, respectively; p < 0.0001). Worth noting, the MIB1 score did not differ significantly when comparing DS with the diffuse areas of PFS, or TFS with the pseudofollicles of PFS. The mean bcl-2 gene protein score was displayed to a high extent in all subtypes, but less extensively by larger activated lymphocytes that, conversely, expressed c-myc. MIB1 score correlated negatively with bcl-2 and positively with c-myc protein scores. These findings suggest that lymphocytes protected from apoptosis by bcl-2 would be exponed to cell activation and growth acceleration provided by c-myc. This condition would account for a different aggressiveness of morphologically activated subtypes, such as TFS and PFS with larger pseudofollicles. The survival analysis, performed in 23 cases, showed a trend of association of cell proliferation and c-myc expression with a more aggressive progression of the disease. Overexpression of p53 and apoptosis were found only in a minority of cases, unrelated to the subtypes. In conclusion, cell growth fraction, bcl-2 and c-myc assessment may be of help in predicting the aggressiveness of different subtypes of SLL. This approach should be most conveniently applied to PFS, which represents a continuum between DS and TFS, in order to distinguish, in this heterogeneous subtype, more indolent from more aggressive disorders.

Idarubicin in patients with diffuse large cell lymphomas: a randomized trial comparing VACOP-B (A = doxorubicin) vs VICOP-B (I = idarubicin).

BACKGROUND AND OBJECTIVE: Idarubicin is an effective drug in acute leukemia but its use in non-Hodgkin lymphomas (NHLs) is not yet well established. We evaluated its efficacy in patients with diffuse large cell lymphoma (DLCL) by means of a randomized trial comparing two 12-week regimens (VACOP-B and VICOP-B) which differed only in the anthracycline drug used (doxorubicin vs idarubicin). METHODS: From January 1992 to December 1994, 104 patients aged less than 65 years with de novo advanced stage DLCL were enrolled. Fifty-two patients were treated with VACOP-B (doxorubicin 50 mg/sqm) and 52 with VICOP-B (idarubicin initially 8 mg/sqm and thereafter 10 mg/sqm). RESULTS: Clinical characteristics of the two groups were not significantly different. One HBsAg+ patient died of hepatic necrosis in the VICOP-B arm, and severe (WHO grade > 2) toxicities occurred in 7 patients treated with VACOP-B and in 5 treated with VICOP-B; the only significant difference was for mucositis (p = 0.02). Complete remission (CR) was obtained in 79% of patients receiving VACOP-B and in 56% (idarubicin 8 mg/sqm) and 75% (idarubicin 10 mg/sqm) of those in the VICOP-B group (p = n.s.). Prognostic factors that negatively affected CR were advanced stage in VACOP, bone marrow infiltration in both schedules. At a median follow-up of two years, overall survival (67% VACOP and 61% VICOP) and disease-free survival (65% and 67%, respectively) were not significantly different. INTERPRETATION AND CONCLUSIONS: Idarubicin is slightly less toxic than doxorubicin; at a dose of 10 mg/sqm the former is easily tolerated and shows the same efficacy as doxorubicin in the treatment of DLCL.

Intensified and high-dose chemotherapy with granulocyte colony-stimulating factor and autologous stem-cell transplantation support as first-line therapy in high-risk diffuse large-cell lymphoma.

PURPOSE: In our previous study with MACOPB, we identified a high-risk group of patients with a poor 3-year survival rate of 29%. These patients were defined as having at diagnosis advanced-stage disease with high tumor burden (TB) and elevated lactate dehydrogenase (LDH) level or bone marrow (BM) involvement. A novel therapeutic scheme was investigated to improve the outcome of these patients. PATIENTS AND METHODS: Fifty patients with high-risk diffuse large-cell lymphoma (DLCL) were enrolled. The therapeutic scheme includes three phases: induction with 8 weeks of MACOPB; intensification with a 3-day course of mitoxantrone 8 mg/m2 plus high-dose cytarabine (HDARA-C) 2 g/m2 every 12 hours plus dexamethasone 4 mg/m2 every 12 hours (MAD protocol) and granulocyte colony-stimulating factor (G-CSF) 5 microg/kg on days 4 to 17 to harvest peripheral-blood progenitor cells (PBPC); consolidation with carmustine (BCNU), etoposide, ARA-C, and melphalan (BEAM) regimen; plus autologous stem-cell transplantation (ASCT) with PBPC, marrow, or both. RESULTS: Thirty-six patients (72%) achieved a complete response (CR), 11 (22%) showed no response (NR), and three (6%) died of toxicity. Among the 22 PRs or NRs after the induction phase, 56% of patients achieved a CR with subsequent intensified therapy. With a median follow-up duration of 32 months, the overall survival and failure-free survival rates were 56% and 50%, respectively. The disease-free survival rate is 69% at 32 months. Leukapheresis after MAD and G-CSF yielded a median of 32 x 10(6)/kg CD34+ cells and 80 x 10(4)/kg granulocyte-macrophage colony-forming units (CFU-GM). Thirty-nine patients were autografted and 11 did not undergo ASCT: six because of disease progression, four due to toxicity, and one because of patient refusal. The median times to achieve engrafment were 11 days (range, 7 to 19) to a neutrophil count greater than 0.5 x 10(9)/L and 12 days (range, 8 to 60) to a platelet count greater than 50 x 10(9)/L. CONCLUSION: This sequential scheme with intensified and high-dose chemotherapy with ASCT is feasible with moderate toxicity and may improve the outcome in high-risk DLCL.

Combined modality treatment with a weekly brief chemotherapy (ACOP-B) followed by locoregional radiotherapy in localized-stage intermediate- to high-grade non-Hodgkin's lymphoma.

BACKGROUND: A cooperative study was undertaken to evaluate the efficacy and toxicity of a very brief course of chemotherapy followed by locoregional radiotherapy in patients with localized-stage intermediate- to high-grade non-Hodgkin's lymphoma (NHL). PATIENTS AND METHOD: From January 1988 to November 1994, 84 patients with localized stages IA and IIA intermediate- to high-grade NHL underwent a combined modality treatment. All patients underwent a six-week chemotherapy regimen, ACOP-B (doxorubicin 50 mg/sqm and cyclophosphamide 350 mg/sqm on weeks 1, 3, 5; vincristine 1.4 mg/sqm and bleomycin 10 mg/sqm on weeks 2, 4, 6; prednisone 50 mg p.o. daily throughout the first two weeks and thereafter every other day), followed by locoregional radiotherapy (36 Gy). RESULTS: The median age was 58 years, with 35% older than 65 years; 52 patients had stage I and 32 stage II; 39 patients had extranodal +/- nodal involvement, and 4 had testicular involvement. Treatment was well tolerated, with only 38% suffering from mild mucositis and no toxic deaths. Seventy-nine patients achieved CR after ACOP-B and 83 at the end of the program. With a median follow-up of four years, relapse-free survival was 79% with 15 relapses (93% disseminated). Two patients with testis lymphoma had CNS relapses. Overall survival was 90% at four years. CONCLUSION: This combined program is effective and probably curative in localized stage intermediate- to high-grade NHL, with low toxicity, also in elderly people. Patients with NHL of the testis, as primary site, require CNS prophylaxis due to the high likelihood of CNS relapse.

Results of a low aggressivity chemotherapy regimen (CVP/CEB) in elderly Hodgkin's disease patients.

BACKGROUND: Hodgkin's disease (HD) after the age of 65 years is uncommon and there are no published data on chemotherapy regimens devised for elderly HD patients. PATIENTS AND METHODS: From 1990 to 1993, 25 elderly HD patients were treated with the CVP/CEB regimen: chlorambucil 6 mg/sqm p.o. days 1 through 7, vinblastine 6 mg/sqm i.v. on day 1, procarbazine 100 mg/sqm p.o. days 1 through 7, prednisone 30 mg/sqm p.o. days 1 through 7, cyclophosphamide 500 mg./sqm i.v. day 15, etoposide 70 mg/sqm i.v. day 15, bleomycin 10 mg/sqm i.v. day 15. Each course was repeated every 4 weeks. Stage I and II patients were treated with 3 courses followed by involved field radiotherapy, while more advanced stage patients received 6 courses and radiotherapy was limited to bulky areas. The results of the CVP/CEB regimen are retrospectively compared to those of 74 elderly patients treated between 1982 and 1989 and subdivided into the following 2 groups: 32 patients treated according to the same therapy used at that time in younger patients, and 42 patients given alternative low aggressivity or palliative treatment. RESULTS: CVP/CEB is a well-tolerated regimen, with only 1 (4%) toxic death and 2 (8%) protocol violations/interruptions. The CVP/CEB complete remission rate (73%) compares favorably with our previous groups of patients, mainly because of the lower toxic death rate. However, the CVP/CEB relapse-free survival rate is lower than that of patients treated with more aggressive conventional regimens (47% vs. 77%, p < 0.02). The CVP/CEB overall survival and event-free survival rates are 55% and 32%, respectively, and they are not statistically different from those of patients treated before 1990. CONCLUSIONS: CVP/CEB is a well-tolerated low toxicity regimen with a high CR rate. The relapse rate is high and event-free survival is comparable to that of patients treated conventionally. Our results suggest the need for individualized treatment criteria for older patients with HD.

The treatment of elderly patients with aggressive non-Hodgkin's lymphomas: feasibility and efficacy of an intensive multidrug regimen.

The results of a prospective trial of an 8 week treatment for elderly patients with advanced intermediate-high grade NHL are reported. Our aim was to reduce general toxicity without losing an antilymphoma effect. For this reason the use of growth factor was studied. We also analysed the behavior of different histological groups (E + F vs G + H). From November 1991 to November 1993 100 patients older than 65 years with combination intermediate-high grade advanced stage NHL were treated with the P-VEBEC regimen, an original including epirubicin 50 mg/sqm, cyclophosphamide 300 mg/sqm and etoposide 100 mg/sqm on weeks 1, 3, 5, 7; vinblastine 5 mg/sqm and bleomycin 5 mg/sqm on weeks 2, 4, 6, 8; prednisone 50 mg/sqm/day per os in the first two weeks and thereafter every other day .46 pts received rG-CSF 5 micrograms/Kg/day throughout the treatment starting on day 2 of every week for 4 consecutive days. Twenty eight pts had B symptoms, 41 had bulky disease, 37 LDH levels above normal, 50 stage IV patients and 30 had bone marrow involvement. Sixty two percent achieved a complete remission (CR). Adverse prognostic factors for CR were E and F histology, stage IV disease, bone marrow infiltration, serum LDH levels above normal, international Prognostic Index (I.I.) intermediate-high and high risk categories and relative dose intensity (RDI) less than 0.80. Severe toxicity was rarely recorded and only one toxic death was observed. With a median follow-up of 33 months OS, DFS and EFS were 44%, 60% and 30% respectively. EFS was influenced by stage, BM involvement, level of LDH and I.I. intermediate-high and high risks. The 52 patients with DLCL (diffuse large cell lymphomas--G + H according to WF) did better with a higher CR, OS, DFS and EFS rates, than the other WF subtypes. In conclusion P-VEBEC is a feasible combination to use in elderly patients, mainly in DLCL. The use of rG-CSF improves the RDI. A RDI > 0.80 could play a role in improving the outcome, especially in patients with adverse prognostic factors. For other subgroups another schedule is probably justified.

Molecular heterogeneity of B-lineage diffuse large cell lymphoma.

B-lineage diffuse large cell lymphoma (B-DLCL) arising de novo is characterized by a marked degree of clinical heterogeneity. To determine whether or not the clinical heterogeneity of de novo B-DLCL is reflected by heterogeneity in the molecular features of these tumors, we investigated the pattern of distribution of several genetic lesions in 70 cases of de novo B-DLCL at diagnosis. The panel of genetic lesions tested comprised the molecular alterations most frequently detected in B-DLCL, including rearrangements of BCL2, BCL6, and MYC as well as deletions of 6q and mutations of TP53. One or more genetic lesions were detected in 39/70 cases of B-DLCL. Isolated structural alterations of BCL2, BCL6, 6q or TPS3 were detected in 8/70, 10/70, 11/70, and 3/70 cases, respectively. No isolated MYC lesions were detected. Six cases carried different combinations of two genetic lesions, including lesions of BCL2 + BCL6 (1 case), BCL2 + MYC (1 case), BCL2 + 6q (2 cases), or BCL6 + 6q (2 cases). One case had accumulated three genetic lesions, namely a rearrangement of BCL2 and BCL6 and a mutation of TPS3. Overall, these data show that multiple distinct patterns of genetic lesions may associate with de novo B-DLCL, indicating that the molecular pathogenesis of this group of lymphomas is characterized by a high degree of molecular heterogeneity.

P-VEBEC: a new 8-weekly schedule with or without rG-CSF for elderly patients with aggressive non-Hodgkin's lymphoma (NHL).

BACKGROUND: Chemotherapy regimens devised for elderly patients with intermediate-high grade NHL are a matter of discussion. The aim is to reduce general toxicity without loosing an antilymphoma effect. The most important limiting factor of chemotherapy is myelotoxicity; for this reason the use of growth factor may be useful in these patients. PATIENTS AND METHODS: From November '91 to November '92, 67 pts older than 65 years with intermediate-and high-grade advanced-stage NHL were treated with the P-VEBEC regimen, an original scheme with epirubicin 50 mg/m2, cyclophosphamide 350 mg/m2 and etoposide 100 mg/m2 on weeks 1, 3, 5, 7; vinblastine 5 mg/m2 and bleomycin 5 mg/m2 on weeks 2, 4, 6, 8, prednisone 50 mg/m2/day p. os in the first 2 weeks and thereafter every other day. Twenty-eight pts received r-GSF 5 micrograms/kg/day throughout the treatment starting on day 2 of every week for 4 consecutive days. Their median age was 71 years (65-80), 31 pts were male and 36 female, histology according W.F. was D 6; E 17; F 16; G 19; H 9. Twenty-five percent of pts had B symptoms, 35% had bulky disease, 41% LDH level > normal, 44% stage IV and 26% had B.M. involvement. RESULTS: C.R. was achieved by 66% of pts. Adverse prognostic factors for CR were E histology, stage IV, bone marrow infiltration and LDH above normal. Severe toxicity was never recorded, no toxic death was observed. With a median follow-up of 24 months OS, DFS and EFS were 55%, 52%, and 33%, respectively. EFS was influenced by stage, BM involvement and level of LDH. The relative dose intensity (RDI) was calculated by the method of Hryniuk and Bush. Patients who received rG-CSF had a significantly higher median RDI (94% vs 79%) and lower myelotoxicity (neutrophil nadir < 500 18% vs 56%). The rate of CR was influenced by RDI > 80% (89% vs 56%). EFS was also better in pts who received a RDI higher than 80% (50% vs 18% p = 0.05). CONCLUSION: P-VEBEC is a feasible cycle in elderly patients; the use of rG-CSF improves RDI. In patients with adverse prognostic factors (BM involvement, poor performance status) a RDI > 0.80 could play a role in improving the outcome.