Pier Luigi Zinzani

Activity of Oral Fludarabine Phosphate in Previously Treated Chronic Lymphocytic Leukemia

PURPOSE A prospective, multicenter, open-label phase II clinical trial was conducted to assess the efficacy and safety of oral fludarabine phosphate. Reference to an historical group of patients treated with the intravenous (IV) formulation allowed the investigators to compare the two formulations. PATIENTS AND METHODS Efficacy was assessed using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) and National Cancer Institute (NCI) criteria for complete remission (CR), partial remission (PR), stable disease, or disease progression. Safety monitoring included World Health Organization (WHO) toxicity grading for all adverse events. RESULTS Seventy-eight (96.3%) of 81 recruited patients with previously treated B-cell chronic lymphocytic leukemia (CLL) received 10-mg tablets of fludarabine phosphate to a dose of 40 mg/m(2)/d for 5 days, repeated every 4 weeks, for a total of six to eight cycles. According to IWCLL criteria, the overall remission rate was 46.2% (CR, 20.5%; PR, 25.6%). The comparative figures using NCI criteria were 51.3% (CR, 17.9%; PR, 33.3%). Overall, 30 incidents of severe adverse events were reported for 22 patients. WHO grade 3 or grade 4 hematologic toxicities included granulocytopenia (53.8%), leukocytopenia (28.2%), thrombocytopenia (25.6%), and anemia (24.4%). Gastrointestinal adverse events were more common with the oral formulation than previously reported with IV fludarabine phosphate. However, these events were generally mild to moderate. CONCLUSION This study demonstrates that oral fludarabine phosphate has similar clinical efficacy to the IV formulation and a safety profile that is both predictable and essentially similar to that of the IV formulation.

Primary follicular and marginal-zone lymphoma of the breast: clinical features, prognostic factors and outcome: a study by the International Extranodal Lymphoma Study Group

BACKGROUND Primary breast lymphoma (PBL) of low-grade histology is a rare disease. This multicentric retrospective study was carried out to determine clinical features, prognosis and relapse. PATIENTS AND METHODS Patients with histologically proven, previously untreated follicular or marginal-zone PBL (MZL PBL) diagnosed from 1980 to 2003 were included in the study. Major end points were progression-free survival (PFS), overall survival (OS) and potential prognostic factors. RESULTS We collected data on 60 cases of PBL [36 follicular and 24 marginal-zone lymphoma (MZL)]. Stage was I(E) or II(E) in 57 patients and IVE in three patients due to bilateral breast involvement. Surgery, chemotherapy and radiotherapy (RT), alone or in combination, were used as first-line treatments in 67%, 42% and 52% of patients, respectively. Overall response rate was 98%, with a 93% complete response rate. Five-year PFS were 56% for MZL and 49% for follicular PBL (P = 0.62). Relapses were mostly in distant sites (18 of 23 cases); no patients relapsed within RT fields. CONCLUSIONS Our data showed an indolent behaviour of MZL PBL, comparable to other primary extranodal MZL. Conversely, patients with follicular PBL had inferior PFS and OS when compared with limited-stage nodal follicular non-Hodgkins lymphomas, suggesting an adverse prognostic role of primary breast localisation in this histological subgroup.

Fludarabine-mitoxantrone combination-containing regimen in recurrent low-grade non-Hodgkin's lymphoma

BACKGROUND The promising results of fludarabine (FLU) in chronic lymphocytic leukemia have prompted its extensive evaluation in low-grade non-Hodgkins lymphoma (LG-NHL). Its different mechanisms of action make FLU an attractive partner for combination with other cytostatic agents. PATIENTS AND METHODS We used a three-drug combination of FLU (25 mg/m2 i.v. on days one to three), mitoxantrone (10 mg/m2 i.v. on day one) and prednisone (40 mg given orally on days one to five) (FMP) to treat 48 patients with recurrent LG-NHL. RESULTS Of the 48 patients, 17 (35%) achieved complete responses (CR), 23 (48%) partial responses, while the remaining 8 (17%) showed no benefit from the treatment. The risk of lower CR rate was significantly correlated with the presence of advanced stage (IV) (P = 0.01), the number of previous regimens (> or = 3) (P = 0.006), and the follicular histologic subtype (P = 0.02). The major toxic effects observed were neutropenia and infections; there was only one fatality, due to drug-related side effects. CONCLUSIONS These data confirm the significant efficacy of the FMP fludarabine-mitoxantrone combination regimen in obtaining a good remission rate with moderate toxicity in a particular subset of recurrent LG-NHL.

Nongastrointestinal mucosa-associated lymphoid tissue (MALT) lymphomas: Clinical and therapeutic features of 24 localized patients

BACKGROUND Peripheral B-cell lymphoma of the marginal zone (MALT, low-grade), presenting as localized, extranodal disease, usually affects the elderly. The gastrointestinal tract is the most frequently involved extranodal location, representing 70% of all MALT lymphomas. Recently, numerous other extranodal sites involved by MALT lymphomas have also been described. PATIENTS AND METHODS From January 1990 to October 1995, 24 patients with untreated nongastrointestinal low-grade MALT lymphoma were submitted to treatments ranging from the local approach of radiotherapy and local alpha-interferon (alpha-IFN) administration to chemotherapy. The tumours were located in the lung (seven cases), conjunctiva (four cases), lachrymal gland and orbital soft tissue (four cases), salivary glands (three cases), skin (three cases), breast (two cases), and thyroid (one case). All patients had low-grade stage IE tumours. RESULTS Chemotherapy was administered in 11 patients (six with lung, three with salivary gland, one with breast, and one with thyroid locations); radiation therapy was employed in seven patients (three with lachrymal gland, three with skin, and one with breast locations); local alpha-IFN administration was administered in five patients (four with conjunctival, and one with lachrymal gland sites); and surgery was employed in one patient with a lung tumour. All patients achieved complete remissions; three local recurrences and two relapses in other sites were observed. The global five-year survival rate was 100% with a relapse-free survival rate of 79%. CONCLUSIONS These data confirm the significant efficacy of different therapeutic approaches to specific sites inbes obtaining a good remission rate for nongastrointestinal localized low-grade MALT lymphomas.

Efficacy of fludarabine and mitoxantrone (FN) combination regimen in untreated indolent non-Hodgkin's lymphomas

PURPOSE In the last years, fludarabine (FLU) alone or in combination with other drugs has been reported to be effective in the treatment of previously treated low-grade non-Hodgkins lymphomas (LG-NHL). The aim of this study was to define the therapeutic efficacy and toxicity of a combination of FLU and mitoxantrone (FN regimen) in untreated LG-NHL. PATIENTS AND METHODS We used a two-drug combination of FLU (25 mg/m2 i.v. on days 1 to 3) and mitoxantrone (10 mg/m2 i.v. on day 1) to treat 27 previously untreated patients with LG-NHL, Chemotherapy was repeated every four weeks for a total of six cycles. Among 27 patients, 17 (63%) were diagnosed with follicular, 6 (22%) with small lymphocytic, and 4 (15%) with immunocytoma subtypes. RESULTS Of the 27 patients, 18 (67%) achieved complete response (CR) and 6 (22%) partial response, while the remaining 3 (11%) showed no benefit from the treatment. Regarding histology, in the follicular subtype we observed an overall response rate of 94%, with a 76.5% CR rate. The estimated two-year relapse-free survival was 83%, and overall survival was 92%. Hematologic grade 3-4 toxicity was seen in only five (3.3%) patients; no opportunistic infections or deaths were associated with the administration of the FN regimen. CONCLUSIONS These preliminary data show that the FN regimen is a very active, well-tolerated combination chemotherapy for untreated patients with advanced LG-NHL.

Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma

Abstract Background Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the α- and δ-isoforms. Patients and methods This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. Results Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2–138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort; median progression-free survival was 294 days (range 0–874) and 70 days (range 0–897), respectively; median duration of response was 390 days (range 0–825) and 166 days (range 0–786), respectively. Common adverse events included hyperglycemia (57.1%; grade ≥3, 23.8%), hypertension (54.8%; grade ≥3, 40.5%), and diarrhea (40.5%; grade ≥3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. Conclusion Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing. This trial is registered with ClinicalTrials.gov number NCT01660451 (Part A).

T-cell prolymphocytic leukaemia: Does the expression of CD8+ phenotype justify the identification of a new subtype? Description of two cases and review of the literature

T-cell chronic lymphocytic leukaemia (T-CLL) has recently been reclassified under the heading of T-cell prolymphocytic leukaemia (T-PLL) because of its unfavourable clinical course, independently of the morphologic features. This rare neoplasm usually shows CD4+/CD8- phenotype. Herein we report on two cases of T-PLL with CD8 expression that correspond to a possible variant of the disease first proposed by Hui et al. in 1987. These cases presented with malignant cells showing immunophenotypic features that can be easily identified and distinguished from other peripheral T-cell leukemias. However, the total number of cases studied is inadequate for defining a discrete clinico-pathologic entity with characteristic clinical features and cytogenetical abnormalities. An international collaboration in which tissue from similar cases is referred to a central pathologist for immunophenotyping and cytogenetical study, and clinical data are centrally compiled, may assist in defining this rare malady as a discrete clinico-pathologic entity.

Diffuse large B-cell lymphoma with primary retroperitoneal presentation: Clinico-pathologic study of nine cases

UNLABELLED Diffuse large B-cell lymphoma primarily presenting in the retroperitoneum (PRLBCL) has been the object of occasional reports, all based on dated techniques. MATERIALS AND METHODS Nine PRLBCLs--with clinical information and paraffin blocks available--were reviewed on morphologic, immunohistochemical and molecular grounds. RESULTS At microscopic examination, the cases were characterized by a diffuse proliferation of large cells (CD20+, CD79a+, CD3-), displaying a wide rim of cytoplasm (clear in seven instances and acidophilic in two), associated with sclerosis and frequent compartmentalization. Phenotypic and molecular analyses showed that: a) three cases were bcl-2+, bcl-6+, HLA-DR+, and CD10+ (1/3), with associated follicular dendritic cell (FDC) component and bcl-2 gene rearrangements; b) four cases were bcl-2, bcl-6, HLA-DR, CD10, FDC, and bcl-2 gene rearrangement negative; c) two cases had border-line characteristics (bcl-2+, bcl-6+, FDC+, HLA-DR-, CD10-, and bcl-2 gene rearrangement-). The first subgroup was thought to be of follicular derivation, as was the third due to bcl-6 and FDC stains. Of the corresponding five patients, three are in complete remission and two died of disease within 12 months. No obvious, normal counterpart was detected in the remaining four tumors: the corresponding patients died of disease in 3-23 months. The problem of similarities between PRLBCL and primary mediastinal LBCL is discussed. CONCLUSIONS Although the present series is small, our findings suggest that PRLBCL may represent a more heterogeneous group of tumors than previously thought, which merits further phenotypic and molecular studies to broaden the understanding of its histogenesis and behavior.