Pier Paolo Fattori

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.

Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial

BACKGROUND Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. METHODS REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m(2) intravenous rituximab, 750 mg/m(2) intravenous cyclophosphamide, 50 mg/m(2) intravenous doxorubicin, and 1·4 mg/m(2) intravenous vincristine on day 1, and 40 mg/m(2) oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. FINDINGS 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. INTERPRETATION Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. FUNDING Fondazione Italiana Linfomi and Celgene.

Staging of Breast Cancer: New Recommended Standard Procedure

AbstractBackground. Staging procedures used to detect metastatic breast cancer at the time of diagnosis are bone scan (BS), chest X-ray (CXR), liver ultrasonography (LUS) and laboratory parameters (LP). These procedures are expensive and not all patients need them. We aimed to identify groups of patients with different risks for metastatic disease. Methods. We reviewed data from 1,218 consecutive cases of breast cancer. Pathological and biological param-eters and instrumental procedures performed at the time of diagnosis and during 6 months of follow-up were recorded. True positive and negative, false positive and negative cases were evaluated. All cases were grouped on the basis of tumour size, nodal involvement, biological characteristics, menopausal status and age. Results. We observed 46 (3.8%) true positive cases with metastatic disease at the time of diagnosis. Documenta-tion relating to BS, CXR and LUS was available for 1,193, 1,206 and 1,206 patients, respectively, with 37 (3.1%), 8 (0.7%) and 10 (0.8%) true positive tests. Logistic regression analysis showed significant odds ratio estimates for pT status and nodal status, thus highlighting the role of these morphological data. These findings suggest that breast cancer patients can be divided into two subgroups: first group pT1-3N0-1, with ≤3 involved nodes, and second group pT1-3N1 with ≥4 involved nodes, pT4 and pN2 (metastases detection rate 1.46 and 10.68%, respectively). In the former group the appropriate procedures of staging would only be laboratory parameters, whereas in the latter group BS, CXR, LUS, LP and tumour markers CEA and CA15.3 would be necessary. Conclusions. The standard staging procedures to detect metastatic disease at breast cancer diagnosis require modification. On the basis of the literature data and our findings, the full staging procedure is appropriate in the second group of patients.

Acute Disseminated Intravascular Coagulation Syndrome in Cancer Patients

Hemostatic abnormalities are rather frequent in cancer patients either in hematological or in solid tumors. Acute disseminated intravascular coagulation (DIC) is a rare coagulopathy in cancer patients, but when it develops it becomes rapidly fatal. Between June 1988 and December 1992 we observed 8 cases of acute DIC occurring in gastric cancer (4 patients), breast cancer (3 patients) and high-grade non-Hodgkin lymphoma (1 patient). In 3 patients affected by gastric carcinoma, acute DIC was the first manifestation of the presence of the tumor, while in the other patients DIC occurred during the course of the disease. All the patients were treated with heparin, fresh frozen plasma and platelet support, but only in 1 patient was a short duration improvement of clinical conditions and coagulation tests recorded. Acute DIC can be the first manifestation of gastric tumors and the presence of the hemorrhagic syndrome associated with thrombocytopenia, hypofibrinogenemia and fibrin/fibrinogen degradation products should initiate a search for gastric carcinoma.

Malignant pericardial mesothelioma. Report of two cases, review of the literature and differential diagnosis.

Malignant pericardial mesothelioma is an uncommon variety of a primary malignant cardio-pericardial tumor and it is a highly lethal and fortunately rare cardiac neoplasm. The presentation of pericardial mesothelioma is aspecific and pathologically mesothelioma is not the most common among primary tumors of the pericardium. It is characterized by atypical solid growth of mesothelium with formation of atypical cavities surrounded by fibrous stroma. Antemortem diagnosis is difficult and distant metastases are extremely rare. Radical surgery can be used to treat localized mesothelioma. The treatment for advanced primary pericardial mesothelioma is usually palliative because the tumor is resistant to radiotherapy and chemotherapy. The prognosis is unfavorable. The median survival from the onset of symptoms is six months. In this paper we report two cases of patients with primary mesothelioma of the pericardium without a definite history of asbestos exposure.

Treatment of primary or metastatic pleural effusion with intracavitary cytosine arabinoside and cisplatin: A phase II study

Thirty-three patients with microscopically verified primary or metastatic malignant pleural effusion were studied: 7 had malignant mesothelioma and 26 metastatic pleural disease. The treatment was based on biochemical and clinical studies which show a synergy between cytosine-arabinoside (Ara-C) and cisplatin. These drugs were instilled in the pleural cavity at the dose of 100 mg for Ara-C and 100 mg/m2 for cisplatin. The cavity was drained after 4 h. If it was possible, the treatment was repeated weekly for 3 times and, after a 6-week rest, it could be started again with the same schedule. The overall response rate (complete plus partial remissions) was 74%. Toxicity was mild or moderate. We conclude that the combination of Ara-C and cisplatin is well tolerated and produces a high response rate in the treatment of malignant pleural effusions.

Lenalidomide monotherapy in heavily pretreated patients with non-Hodgkin lymphoma: an Italian observational multicenter retrospective study in daily clinical practice

Abstract Clinical trial results indicate that lenalidomide, an immunomodulatory drug, is a promising treatment in relapsed/refractory non-Hodgkin lymphoma (NHL). This retrospective multicenter study was conducted in patients with relapsed/refractory NHL treated with lenalidomide monotherapy through a Named Patient Program in Italy. Principal endpoints were overall response rate (ORR), safety and overall survival (OS). The ORR in 64 evaluable patients was 42.2% and was similar among patients receiving 10, 15 or 25 mg/day lenalidomide. Response rates in patients with mantle cell, diffuse large B-cell and follicular lymphoma were 45.5%, 42.1% and 20%, respectively. Among patients who responded to most recent prior therapy, ORR was 50.0% versus 36.8% in patients with refractory NHL. Mean duration of response in patients receiving any lenalidomide dose was 10.5 months; 1-year progression-free survival and OS were 50.3% and 82.6%, respectively. These findings suggest that lenalidomide is effective and safe for heavily pretreated patients with NHL in the clinical setting.

IL-17/IL-10 double-producing T cells: new link between infections, immunosuppression and acute myeloid leukemia

BackgroundAcute myeloid leukemia (AML) is an incurable disease with fatal infections or relapse being the main causes of death in most cases. In particular, the severe infections occurring in these patients before or during any treatment suggest an intrinsic alteration of the immune system. In this respect, IL-17-producing T helper (Th17) besides playing a key role in regulating inflammatory response, tumor growth and autoimmune diseases, have been shown to protect against bacterial and fungal pathogens. However, the role of Th17 cells in AML has not yet been clarified.MethodsT cell frequencies were assessed by flow cytometry in the peripheral blood of 30 newly diagnosed AML patients and 30 age-matched healthy volunteers. Cytokine production was determined before and after culture of T cells with either Candida Albicans or AML blasts. Statistical analyses were carried out using the paired and unpaired two-tailed Student’s t tests and confirmed with the non parametric Wilcoxon signed-rank test.ResultsA strong increase of Th17 cells producing immunosuppressive IL-10 was observed in AML patients compared with healthy donors. In addition, stimulation of AML-derived T cells with a Candida albicans antigen induced significantly lower IFN-γ production than that observed in healthy donors; intriguingly, depletion of patient Th17 cells restored IFN-γ production after stimulation. To address the role of AML blasts in inducing Th17 alterations, CD4+ cells from healthy donors were co-cultured with CD33+ blasts: data obtained showed that AML blasts induce in healthy donors levels of IL-10-producing Th17 cells similar to those observed in patients.ConclusionsIn AML patients altered Th17 cells actively cause an immunosuppressive state that may promote infections and probably tumor escape. Th17 cells could thus represent a new target to improve AML immunotherapy.

Immunoglobulin V(H) genes and CD38 expression analysis in B-cell chronic lymphocytic leukemia.

a more stringent cutoff of 7% provided the best separation for different prognostic groups [7] . Since both the IgV H mutational status and CD38 expression have been proposed as strong independent prognostic markers of outcome [5] , in the current study, the V H mutation status and CD38 expression were analyzed in 52 B-CLL patients at diagnosis to clarify their correlation. Clinical diagnosis of B-CLL was based on standard morphologic and immunophenotypic criteria (CD19+/ CD5+, CD19+/CD23+, weak sIg+). The median age at diagnosis was 64 years; the male/female ratio was 1.7, and the clinical risk category in most cases was Rai stage O or I. Gene analysis and immunophenotypic analysis were performed on peripheral blood samples. IgV H mutation status was evaluated by polymerase chain reaction using a consensus 5 FR1 region primer together with a consensus 3 JH region primer. PCR products were sequenced using the BigDye Terminator Cycle Sequencing Reaction kit (Applied Biosystems) and analyzed with an automated DNA sequencer (ABI Prism 310). Nucleotide sequences were aligned with those in the BlastN database. Unmutated immunoglobulin sequences were defi ned as sequences with 2% or less deviation from any germ line IgV H sequence. The V H family gene utilized in the 52 paB-cell chronic lymphocytic leukemia (B-CLL) cases can be divided into two subgroups based on the presence or absence of signifi cant numbers of mutations in the variable region of the immunoglobulin heavy chain (IgV H ) genes [1] . B-CLL is a heterogeneous disease: patients whose leukemic cells express unmutated IgV H regions often have progressive disease and show resistance to chemotherapy treatment, whereas patients whose leukemic cells express mutated IgV H regions more often have an indolent disease and respond to chemotherapy treatment [2, 3] . However, the clinical usefulness of IgV H gene mutation analysis is offset by the high costs and the level of expertise required for this technique. Many reports suggest that in B-CLL CD38 expression on B-cells may be a surrogate marker of the IgV H gene status: high CD38 expression levels were found to correlate with the presence of unmutated V H genes and low CD38 expression levels with mutated V H genes [2, 4] . Currently, however, the usefulness of this marker in B-CLL is subject to controversy [5, 6] . Some of the differences may be due to technical aspects of the CD38 assay and the choice of an optimal cutoff point for the number of CD38+ cells. Various studies considered B-CLL cases with 30% or more cells expressing CD38 to be CD38+ [2, 5] , but in a larger study Received: January 18, 2005 Accepted after revision: July 11, 2005

CARBOPLATIN AND GEMCITABINE IN THE PALLIATIVE TREATMENT OF STAGE IV NON-SMALL CELL LUNG CANCER: DEFINITIVE RESULTS OF A PHASE II TRIAL

Background Cisplatin-containing regimens represent the gold standard in the treatment of advanced non-small cell lung cancer, but carboplatin is often preferred for its better toxic profile when palliation is the aim of the treatment. The synergistic effect and tolerability of carboplatin-gemcitabine combination are well known. In this phase II trial, we evaluated the activity and safety of a schedule with carboplatin and gemcitabine, defined in our previous phase I trial. Methods Thirty-seven patients with measurable stage IV non-small cell lung cancer were treated with carboplatin, AUC 4.5 mg/ml/min on day 1, and gemcitabine, 800 mg/m2 on days 1 and 8, every 21 days. All patients were treated until disease progression or intractable toxicity and were evaluated before each course of chemotherapy for toxicity and after every 3 courses for response. Results After a median follow-up of over 10 months, complete response, partial response, and stabilization of the disease were observed in 3 (8.1%), 9 (24.3%), and 15 patients (40.5%), respectively. Median time to progression was 7 months. At this writing, 27 patients have died, with a median survival of 10 months, and 29 (78.3%), 16 (43.2%), and 11 (29.7%) patients are alive after 6, 12, and 15 months of follow-up, respectively. Toxicity was mild, and mainly hematological, with a significant correlation with the number of courses of chemotherapy (P = 0.0003). Conclusions Our results are comparable with those reported in the literature and confirm the good activity and tolerability of the carboplatin-gemcitabine combination. Up to 4 courses of chemotherapy with carboplatin and gemcitabine may represent an interesting option in the palliative treatment of non-small cell lung cancer.