Amalia De Renzo

Fludarabine Plus Mitoxantrone With and Without Rituximab Versus CHOP With and Without Rituximab As Front-Line Treatment for Patients With Follicular Lymphoma

PURPOSE Promising new therapeutic options for follicular lymphoma (FL) include fludarabine plus mitoxantrone (FM) and the mouse/human anti-CD20 antibody, rituximab. We performed a randomized comparative trial of FM with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) front-line chemotherapy with and without sequential rituximab. PATIENTS AND METHODS All previously untreated CD20(+) FL patients presenting in 15 Italian cooperative institutions from October 1999 were randomly allocated to FM or CHOP. Following clinical or molecular restaging, patients in complete remission (CR) with bcl-2/IgH negativity (CR(-)) received no further treatment; those in CR with bcl-2/IgH positivity (CR(+)) received rituximab, as did those in partial remission (PR) with bcl-2/IgH negativity (PR(-)) or positivity (PR(+)); nonresponders (NR subgroup) were off study. RESULTS After chemotherapy, the FM arm achieved higher rates of CR (68% [49 of 72 patients] v 42% [29 of 68 patients]; P =.003) and CR(-) (39% [28 of 72 patients] v 13 of 68 patients [19%]; P =.001). Rituximab elicited CR(-) in 55 of 95 treated patients (58%). The final CR(-) rate was higher in the FM arm (71% [51 of 72 patients] v 51% [35 of 68 patients]; P =.01). However, with a median follow-up of 19 months (range, 9 to 37 months), no statistically significant difference was found among the various study arms in terms of both progression-free (PFS) and overall survival (OS). CONCLUSION These results indicate that FM is superior to CHOP for front-line treatment of FL and that rituximab is an effective sequential treatment option. However, they also confirm that this superiority is unlikely to translate into either better PFS or OS.

Early Autologous Stem-Cell Transplantation Versus Conventional Chemotherapy as Front-Line Therapy in High-Risk, Aggressive Non-Hodgkin’s Lymphoma: An Italian Multicenter Randomized Trial

PURPOSE To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease. RESULTS The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P =.95), 5-year progression-free survival was 49% and 61% (P =.21), and 5-year relapse-free survival was 65% and 77% (P =.22), respectively. CONCLUSION Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients.

Randomized comparison of consolidation radiation versus observation in bulky Hodgkin's lymphoma with post-chemotherapy negative positron emission tomography scans

This study aimed at evaluating the role of consolidation radiation in a setting of Hodgkins lymphoma (HL) patients, using event-free survival (EFS) as end point. Among 260 patients treated with induction chemotherapy for bulky HL, 160 patients achieved negative residual masses at 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scans. They were randomly divided into two well-matched groups to receive either 32 Gy radiotherapy to bulky area or no further therapy. At a median follow-up of 40 months, histology showed a malignancy in 14% of patients in the chemotherapy-only group (HL, 11 patients) and in 4% of patients in the chemotherapy + radiotherapy group (HL, 2 patients; carcinoma in previously irradiated area, 1 patient) (P = 0.03). All the relapses in the chemotherapy-only group involved the bulky site and the contiguous nodal regions. Thus, the overall diagnostic accuracy of FDG-PET to exclude future relapses in the patients nonprotected by radiotherapy was 86% with a false-negative rate of 14%. Our study suggests that the addition of irradiation helps improve EFS in HL patients with post-chemotherapy FDG-PET-negative residual masses.

Randomized Trial of Fludarabine Versus Fludarabine and Idarubicin as Frontline Treatment in Patients With Indolent or Mantle-Cell Lymphoma

PURPOSE A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas. PATIENTS AND METHODS From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 3 and idarubicin 12 mg/m(2) on day 1). RESULTS In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P =.021). CONCLUSION Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.

Antiviral therapy after complete response to chemotherapy could be efficacious in HCV-positive non-Hodgkin’s lymphoma

BACKGROUND/AIMS Prevalence of HCV infection in non-Hodgkins lymphoma is high. The impact of antiviral therapy on the natural history of this subgroup of lymphomas after a successful chemotherapy regimen is still an argument of debate. METHODS We retrospectively examined 343 chemotherapy-treated patients referred to our centre for five consecutive years. Clinical and histological characteristics, disease free-survival (DFS) and overall-survival (OS) were compared in HCV-positive (69/343) and HCV-negative (274/343) patients. Twenty-five HCV-positive patients received antiviral treatment following chemotherapy discontinuation. Uni- and multivariate analyses were performed. RESULTS 20% of lymphomas were HCV-positive. Indolent histology was prevalent in the HCV-positive group (p<0.05); no significant differences in OS or DFS were found between the two groups; in HCV-positive subjects, antiviral therapy, was associated with a longer DFS (p<0.05); none of the HCV-positive subjects who achieved a virological response experienced any lymphoma relapse; 29% of non responders did; at multivariate analysis, the independent factors related to a better clinical outcome were: indolent histology at the onset of lymphoma and antiviral therapy. CONCLUSIONS Antiviral treatment in HCV-positive non-Hodgkins lymphoma may be an important strategy to reinforce the results of a successful chemotherapy regimen; further studies are needed to validate this combined approach.

The addition of rituximab to anthracycline‐based chemotherapy significantly improves outcome in ‘Western’ patients with intravascular large B‐cell lymphoma

Some case reports and a Japanese series suggest benefit from the use of rituximab in patients with intravascular large B‐cell lymphoma (IVL). Rituximab efficacy was evaluated in Western patients with IVL, comparing outcome of 10 patients treated with rituximab + chemotherapy (R‐CT) and of 20 patients treated with chemotherapy alone (CT). There were no significant differences in patients’ characteristics between the two subgroups. The addition of rituximab was associated with improved complete remission rate (90% vs. 50%; P = 0·04), event‐free survival (3‐year: 89% vs. 35%; P = 0·003) and overall survival (3‐year: 89% vs. 38%; P = 0·01). In conclusion, rituximab may substantially change the dismal prognosis of IVL.

Rituximab Maintenance Compared With Observation After Brief First-Line R-FND Chemoimmunotherapy With Rituximab Consolidation in Patients Age Older Than 60 Years With Advanced Follicular Lymphoma: A Phase III Randomized Study by the Fondazione Italiana Linfomi

PURPOSE To evaluate the efficacy of rituximab maintenance in 60- to 75-year-old patients with advanced follicular lymphoma responding to brief first-line chemoimmunotherapy followed by rituximab consolidation. PATIENTS AND METHODS A total of 234 treatment-naive 60- to 75-year-old patients began chemoimmunotherapy with four monthly courses of rituximab, fludarabine, mitoxantrone, and dexamethasone (R-FND) followed by four weekly cycles of rituximab consolidation. Of these, 210 patients completed the planned treatment, and 202 responders were randomly assigned to rituximab maintenance (arm A) for 8 months, once every 2 months for a total of four doses, or to observation (arm B). RESULTS Median ages in arms A and B were 66 and 65 years, respectively. After induction and consolidation therapy, the overall response rate was 86%, with 69% complete remissions (CR). After a 42-month median follow-up from diagnosis, 3-year progression-free survival (PFS; the primary end point) and overall survival (OS) were 66% (95% CI, 59% to 72%) and 89% (95% CI, 85% to 93%), respectively. After randomization, 2-year PFS was 81% for rituximab maintenance versus 69% for observation, with a hazard ratio of 0.74 (95% CI, 0.45 to 1.21; P = .226), although this was not statistically significant. No differences between the two arms were detected for OS. Overall, the regimen was well-tolerated. The most frequent grade 3 to 4 toxicity was neutropenia (25% of treatment courses), with 13 infections. Two toxic deaths (0.8%) occurred during induction treatment. CONCLUSION A brief R-FND induction plus rituximab consolidation achieved excellent results with high CR and PFS rates, supporting the feasibility of this regimen in patients older than 60 years. A short rituximab maintenance did not achieve a statistically significant PFS improvement over observation.

Chlamydia psittaci in ocular adnexa MALT lymphoma: a possible role in lymphomagenesis and a different geographical distribution

Ocular adnexa MALT-lymphomas represent approximatively 5-15% of all extranodal lymphomas. Almost 75% of OAMLs are localized in orbital fat, while 25% of cases involves conjunctive. MALT-lymphomas often recognize specific environmental factors responsible of lymphoma development and progression. In particular as Helicobacter pylori in gastric MALT lymphomas, other bacterial infections have been recognized related to MALT lymphomas in specific site. Recently Chlamydia psittaci has been identified in Ocular Adnexa MALT lymphomas, with variable frequence dependently from geographic areas. Thus bacterial infection is responsible of clonal selection on induced MALT with subsequent lymphoma development. Moreover Chlamydia psittaci could promote chromosomal aberration either through genetic instability as a consequence of induced proliferation and probably through DNA oxidative damage. The most common translocation described in MALT lymphomas affects NF-kB pathway with a substantial antiapoptotic effect. Several therapeutic approaches are now available, but the use of antibiotic-therapy in specific cases, although with conflicting results, could improve the treatment of ocular adnexa MALT lymphomas. In this review we analyse the most relevant features of Ocular adnexa MALT lymphomas, underlining specific biological characteristics mainly related to the potential role of Chlamydia psittaci in lymphomagenesis.

Excellent prognosis and prevalence of HCV infection of primary hepatic and splenic non-Hodgkin’s lymphoma

Background:  Primary Hepatic (PHL) and Primary Splenic (PSL) non‐Hodgkin’s Lymphoma are rare entities. Small series of PHL and PSL have been reported, suggesting a non‐fortuitous association with Hepatitis C Virus (HCV) infection. The prognosis is believed to be dismal, with early recurrence and short survival.

Predictive value of technetium-99m sestamibi in patients with multiple myeloma and potential role in the follow-up

Technetium-99m 2-methoxyisobutylisonitrile (99mTc-MIBI or setamibi) has recently been proposed for use in the evaluation of multiple myeloma (MM). The aims of this study were to investigate its potential predictive value in patients with MM and its possible role in the follow-up. Thirty patients with MM who had undergone two 99mTc-MIBI scintigraphic studies at least 2 months apart constituted the study group; 22 of them received chemotherapy in the interval between the two scans. The scans were classified as showing pattern N when only physiological uptake was present, pattern D when diffuse bone marrow uptake was observed, pattern F when areas of focal uptake of the tracer were evident, and pattern F+D when both D and F patterns were observed. Comparative 99mTc-MIBI scintigraphy was considered indicative of disease progression when there was a worsening of the pattern (i.e. from N to D, or from N or D to F or to F+D) or an increase in the pattern D semiquantitative score. It was considered indicative of disease improvement when the opposite trend was observed; otherwise, it was considered to document a stable condition. A significant association was observed between the baseline scintigraphic pattern and clinical status at follow-up in the group of patients evaluated after chemotherapy (χ2=16.7, P<0.05). A negative baseline 99mTc-MIBI scintigram showed a high predictive accuracy (100%) for remission, while the presence of pattern F or F+D was often associated with a less favourable outcome. A multivariate analysis showed that 99mTc-MIBI uptake pattern has an added value in relation to known prognostic variables such as C-reactive protein. 99mTc-MIBI scintigraphy patterns at follow-up were significantly associated with the clinical status evaluated after chemotherapy (χ2=32.6, P<0.0001). Considering pattern N as indicating remission, pattern D stable condition, and pattern F or F+D progressive disease, a high concordance between scintigraphic findings and clinical status was found in the 22 patients undergoing chemotherapy (91%). Variation in 99mTc-MIBI findings comparing baseline and follow-up evaluations was significantly associated with clinical status both in patients undergoing chemotherapy (χ2=26.5, P<0.0005) and in those not undergoing chemotherapy (χ2=8.0, P<0.005). In conclusion, the results of this study suggest a prognostic value of 99mTc-MIBI scintigraphy in patients with MM and a potential role during the follow-up.