Lapo Alinari

Phase II Trial of Proteasome Inhibitor Bortezomib in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma

PURPOSE To determine the antitumor activity of the proteasome inhibitor bortezomib in patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma unspecified (PTCLU) with isolated skin involvement. PATIENTS AND METHODS From May 2005 to June 2006 at our institute, we treated patients with previously pretreated CTCL or PTCLU using bortezomib as a single agent, at a dose of 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, every 21 days for a total of six cycles. RESULTS Fifteen patients were registered, of whom 12 (10 CTCL, all mycosis fungoides, and two PTCLU with isolated skin involvement) were assessable. The overall response rate was 67%, with two (17%) complete remissions and six (50%) partial remissions. The remaining four patients had disease progression. Histologically, the responder patients were seven with CTCL and one with PTCLU with isolated skin involvement. All responses were durable, lasting from 7 to 14 or more months. Overall, the drug was well tolerated, with no grade 4 toxicity. The most common grade 3 toxicities were neutropenia (n = 2), thrombocytopenia (n = 2), and sensory neuropathy (n = 2). CONCLUSION This study suggests that bortezomib was well tolerated and has significant single-agent activity in patients with cutaneous T-cell lymphoma.

Role of [18F]Fluorodeoxyglucose Positron Emission Tomography Scan in the Follow-Up of Lymphoma

PURPOSE In lymphoma, [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is routinely used for initial staging, early evaluation of treatment response, and identification of disease relapse. However, there are no prospective studies investigating the value of serial FDG-PET over time in patients in complete remission. PATIENTS AND METHODS All patients with lymphoma who achieved the first complete remission were prospectively enrolled onto the study and scheduled for serial FDG-PET scans at 6, 12, 18, and 24 months; further scans were then carried out on an annual basis. Overall, the population included 421 patients (160 patients with Hodgkins lymphoma [HL], 183 patients with aggressive non-Hodgkins lymphoma [NHL], and 78 patients with indolent follicular NHL). All patients had a regular follow-up evaluation, including complete clinical and laboratory evaluation, and final assessment of any suspect FDG-PET findings using other imaging procedures (computed tomography [CT] scan) and/or biopsy and/or clinical evolution. FDG-PET findings were reported as positive for relapse, inconclusive (when equivocal), or negative for relapse. RESULTS PET enabled documentation of lymphoma relapse in 41 cases at 6 months, in 30 cases at 12 months, in 26 cases at 18 months, in 10 cases at 24 months, and in 11 cases at more than 36 months. All 36 patients with inconclusive positive PET underwent biopsy; only 12 (33%) of 36 patients had a concomitant suggestion of positivity on CT. A lymphoma relapse was diagnosed in 24 (66%) of 36 patients. CONCLUSION Our results confirm FDG-PET as a valid tool for follow-up of patients with HL and NHL. In patients with inconclusive positive results, histologic confirmation plays an important role in identifying true relapse.

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.

Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas

PURPOSE Primary cutaneous B-cell lymphomas (PCBCLs) are a distinct group of primary cutaneous lymphomas with few and conflicting data on their prognostic factors. PATIENTS AND METHODS The study group included 467 patients with PCBCL who were referred, treated, and observed in 11 Italian centers (the Italian Study Group for Cutaneous Lymphomas) during a 24-year period (1980 to 2003). All of the patients were reclassified according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification. RESULTS Follicle center lymphoma (FCL) accounted for 56.7% of occurrences, followed by marginal-zone B-cell lymphoma (MZL; 31.4%); diffuse large B-cell lymphoma (DLBCL), leg type, was reported in 10.9% of patients. Radiotherapy was the first-line treatment in 52.5% of patients and chemotherapy was the first-line treatment in 24.8% of patients. The complete response rate was 91.9% and the relapse rate was 46.7%. The 5- and 10-year overall survival (OS) rates were 94% and 85%, respectively. Compared with FCL/MZL, DLBCL, leg type, was characterized by statistically significant lower complete response rates, higher incidence of multiple cutaneous relapses and extracutaneous spreading, shorter time to progression, and shorter OS rates. The only variable with independent prognostic significance on the OS was the clinicopathologic diagnosis according to the WHO-EORTC classification (DLBCL, leg-type, showed a significantly worse prognosis v FCL and MZL; P < .001), whereas the only variable with independent prognostic significance on disease-free survival was the presence of a single cutaneous lesion (P = .001). CONCLUSION Our study identifies a possible PCBCL subclassification and the extent of cutaneous involvement as the two most relevant prognostic factors in PCBCL. These data can be considered reasonably as the clinical background for an appropriate management strategy.

The clinical application of monoclonal antibodies in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) represents the most prevalent adult leukemia. Treatment with chemotherapy over the past 3 decades has been palliative. The introduction of therapeutic antibodies has increased the number of treatment options for this disease. Despite this increase, our true understanding of the mechanism of action of antibody therapy in CLL remains limited. Rituximab, a CD20 antibody, is currently widely used in combination-based strategies for both previously untreated symptomatic CLL and as salvage therapy. Recent data suggest that the addition of rituximab to fludarabine with or without cyclophosphamide prolongs survival in younger patients with CLL. Other improved CD20 antibodies with promising clinical activity, including ofatumumab and GA-101, are coming forward. Alemtuzumab, a CD52 antibody, likewise has demonstrated benefit in both symptomatic, previously untreated CLL and in patients with relapsed disease but has less selectivity. Development of other therapeutic antibodies targeting alternative B-cell-specific antigens in CLL has been less successful, although many promising candidate antibodies and/or small modular immune pharmaceuticals (SMIPs) are coming forward. In addition, recent efforts to combine currently applied therapeutic antibodies with other biologic and targeted therapies with efficacy in CLL offers the potential to move toward alternative non-chemotherapy-based treatment approaches.

Predictive role of positron emission tomography (PET) in the outcome of lymphoma patients

An extensive analysis of the reliability of positron emission tomography (PET) after induction treatment in patients with Hodgkins disease (HD) or aggressive non-Hodgkins lymphoma (NHL). In all, 75 untreated patients with HD (n=41) or aggressive NHL (n=34) were studied with both PET and CT scans following standard chemotherapy induction therapy (ABVD or MACOP-B) with/without radiotherapy. Histopathological analysis was performed when considered necessary. After treatment, four out of five (80%) patients who were PET+/CT− relapsed, as compared with zero out of 29 patients in the PET−/CT− subset. Among the 41 CT+ patients, 10 out of 11 (91%) who were PET+ relapsed, as compared with 0 out of 30 who were PET−. The actuarial relapse-free survival (RFS) rates were 9 and 100% in the PET+ and PET− subsets, respectively (P=0.00001). All five patients who were PET+/CT− underwent a lymph node biopsy: in four (80%) cases, persistent lymphoma and was confirmed at histopathological examination. Two HD patients who were PET−/CT+ (with large residual masses in the mediastinum or lung) were submitted to biopsy, which in both cases revealed only fibrosis. In HD and aggressive NHL patients, PET positivity after induction treatment is highly predictive for the presence of residual disease, with significant differences being observable in terms of RFS. PET negativity at restaging strongly suggests the absence of active disease; histopathological verification is important in patients who show PET positivity.

A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients

BACKGROUND A prospective, single-arm, open-label, nonrandomized phase II combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus radioimmunotherapy trial was conducted to evaluate the efficacy and safety in untreated elderly diffuse large B-cell lymphoma (DLBCL) patients. PATIENTS AND METHODS From February 2005 to April 2006, in our institute we treated 20 eligible elderly (age > or =60 years) patients with previously untreated DLBCL using a novel regimen consisting of six cycles of CHOP chemotherapy followed 6-10 weeks later by (90)Y ibritumomab tiuxetan. RESULTS The overall response rate to the entire treatment regimen was 100%, including 95% complete remission (CR) and 5% partial remission. Four (80%) of the five patients who achieved less than a CR with CHOP improved their remission status after radioimmunotherapy. With a median follow-up of 15 months, the 2-year progression-free survival was estimated to be 75%, with a 2-year overall survival of 95%. The (90)Y ibritumomab tiuxetan toxicity included grade > or =3 hematologic toxicity in 12 of 20 patients; the most common grade > or =3 toxic effects were neutropenia (12 patients) and thrombocytopenia (7 patients). Transfusions of red blood cells and/or platelets were given to one patient. CONCLUSION This study has established the feasibility, tolerability, and efficacy of this regimen for elderly patients with DLBCL.

Fludarabine-Containing Chemotherapy as Frontline Treatment of Nongastrointestinal Mucosa-Associated Lymphoid Tissue Lymphoma

Mucosa‐associated lymphoid tissue (MALT) lymphoma is a specific clinicopathologic entity with gastric and nongastrointestinal site involvement. The authors reported the clinical outcome of patients with Stage IE nongastrointestinal MALT lymphoma treated with a frontline fludarabine‐containing regimen or with a regimen containing cyclophosphamide, vincristine, and prednisone (CVP).

Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.

Extranodal Marginal Zone B-cell Lymphoma of MALT-type of the Lung: Single-center Experience with 12 Patients

The lung is a relatively rare site for mucosa-associated lymphoid tissue (MALT) lymphomas: we report the largest available single-center series of patients with this presentation. From August 1992 to October 2000, 12 patients with untreated primary low-grade MALT lymphoma of the lung were submitted either to chemotherapy alone (n =8), surgery alone (n =2) or surgery plus chemotherapy (n =2). At diagnosis, 6 (50%) were asymptomatic and 6 (50%) had nonspecific pulmonary symptoms. The most common radiologic findings were a pulmonary infiltrate (7 cases) and a mass lesion (5 cases). Histological diagnosis was obtained with transbronchial lung biopsy/bronchoalveolar lavage (BAL) (6 cases), with transthoracic needle biopsy (1 case), or an open thoracotomy (5 cases). All patients had stage IE. All 12 (100%) achieved complete remission; 3 (25%) local recurrences were observed. The global 6-year survival rate was 100% with a relapse-free survival rate of 50%. In conclusion, these data underline the diagnostic utility of BAL and the therapeutic efficacy of a chemotherapeutic strategy based on regimens such as N-CVP in the context of localized MALT lymphoma of the lung.