An open-label, pilot study of fludarabine, cyclophosphamide, and alemtuzumab in relapsed/refractory patients with B-cell chronic lymphocytic leukemia.

Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m² per day, oral cyclophosphamide 250 mg/m² per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.

Modulated chemotherapy according to modified comprehensive geriatric assessment in 100 consecutive elderly patients with diffuse large B-cell lymphoma.

Chemotherapy is associated with toxicity in elderly patients with potentially curable malignancies, posing the dilemma of whether to intensify therapy, thereby improving the cure rate, or de-escalate therapy, thereby reducing toxicity, with consequent risks for under- or overtreatment. Adequate tools to define doses and combinations have not been identified for lymphoma patients. We conducted a prospective trial aimed to evaluate the feasibility and efficacy of chemotherapy modulated according to a modified comprehensive geriatric assessment (CGA) in elderly (aged ≥70 years) patients with diffuse large B-cell lymphoma (DLBCL). In June 2000 to March 2006, 100 patients were stratified using a CGA into three groups (fit, unfit, and frail), and they received a rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone modulated in dose and drugs according to comorbidities and activities of daily living (ADL) and instrumental ADL scores. Treatment was associated with a complete response rate of 81% and mild toxicity: grade 4 neutropenia in 14%, anemia in 1%, and neurological and cardiac toxicity in 2% of patients. At a median follow-up of 64 months, 51 patients were alive, with 5-year disease-free, overall, and cause-specific survival rates of 80%, 60%, and 74%, respectively. Chemoimmunotherapy adjustments based on a CGA are associated with manageable toxicity and excellent outcomes in elderly patients with DLBCL. Wide use of this CGA-driven treatment may result in better cure rates, especially in fit and unfit patients.

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.

Variations in clinical presentation, frequency of hemophagocytosis and clinical behavior of intravascular lymphoma diagnosed in different geographical regions.

BACKGROUND AND OBJECTIVES: This study explored variations in the clinical manifestations of intravascular lymphoma (IVL) on the bases of the association with hemophagocytosis and the country where the diagnosis was made. DESIGN AND METHODS: The clinical features of 50 Western patients with IVL were compared with those of 123 patients with IVL diagnosed in Eastern countries (87 diagnosed in Japan and 36 in other Asian countries), previously reported in English literature, and collected by an electronic bibliographic search. RESULTS: Hemophagocytosis was absent in Western patients, but reported in 38 (44%) Japanese patients (p=0.00001) and in seven (19%) patients from other Asian countries (p=0.002). No clinical differences were evident between patients with hemophagocytosis-negative IVL diagnosed in Western countries, Japan and other Asian Countries. Conversely, Japanese and non-Japanese patients with hemophagocytosis-related IVL more frequently had stage IV disease, fever, hepato-splenic involvement, marrow infiltration, dyspnea, anemia, and thrombocytopenia, and rarely exhibited cutaneous or central nervous system involvement. Lymph node and peripheral blood involvement was uncommon in all subgroups. In Western patients, anthracycline-based chemotherapy was associated with a 52% remission rate, and a 2-year overall survival of 46%. INTERPRETATION AND CONCLUSIONS: The clinical features of IVL vary according to the association with hemophagocytosis, regardless of the country in which the diagnosis is made. Western, Japanese and other Asian patients with hemophagocytosis-negative IVL display similar clinical characteristics and should be considered as having classical IVL. Patients with hemophagocytosis-related IVL show significantly different clinical features. Both forms have a poor prognosis. Extensive molecular studies are needed to explore whether these clinical differences might reflect discordant biological entities within IVL.

Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the feasibility and toxicity of CHOP-14, with rituximab (R-CHOP-14), supported by pegfilgrastim, in untreated diffuse large B-cell lymphoma (DLBCL). DESIGN AND METHODS: This study included 50 patients with DLBCL with a median age of 55 years (range: 22-70). Sixty-two percent had an International Prognostic Index score >1, 40% had bulky disease and 52% had stage IV disease. CHOP was administered every 14 days, preceded on day 1 by rituximab (375 mg/m2) and followed on day 3 by pegfilgrastim (6 mg per cycle). Toxicity was calculated over 277 cycles administered; feasibility was calculated over 227, since the first cycle in each patient was not susceptible to delay or dose-reduction. RESULTS: Therapy was delivered on time in 92% of cycles, with the relative dose intensity being 95% for doxorubicin and cyclophosphamide. Grade 4 neutropenia developed in 19% of cycles and neutropenic fever in 4% of cycles (16% of patients), with a median duration of 3 days (range: 2-10). The program was completed in 40 of 50 patients (80%); reasons for withdrawal included progression in three patients, interstitial pneumonia in four, prolonged severe neutropenia in two and septic shock in one patient. Severe adverse events occurred on 12 occasions (4% of cycles), involving 11 patients (22% of total); the most frequent severe adverse event was interstitial pneumonia which occurred in seven patients (14% of total). In three cases, Pneumocystis carinii pneumonia was documented; no cotrimoxazole prophylaxis had been given and a correlation with hypogammaglobulinemia was observed. The complete remission rate was 74%; the 2-year event-free and overall survival rates were 72% and 68%, respectively. INTERPRETATION AND CONCLUSIONS: A single dose of pegfilgrastim per cycle of R-CHOP allowed on-time delivery of this chemotherapy in DLBCL, with a low incidence of febrile neutropenia; the risk of P. carinii pneumonia makes cotrimoxazole prophylaxis essential in this setting.

The VAD-DCEP sequence is an effective pre-transplant therapy in untreated multiple myeloma.

BACKGROUND AND OBJECTIVES: Standard treatment for patients with multiple myeloma is debulking chemotherapy with non-alkylating agents followed by a regimen to mobilize peripheral blood stem cells (PBSC) and the transplantation of the mobilized, autologous PBSC. The aim of this study was to evaluate the efficacy of a new regimen and compare it with that of a previous regimen. DESIGN AND METHODS: In a large cohort of 106 patients (group I) we administered a new pre-transplant program which includes 2 courses of pulsed-VAD (vincristine, adriamycin, dexamethasone) followed by 2 courses of DCEP (dexamethasone, cyclophosphamide, etoposide and cis-platinum). We compared the efficacy of this new VAD-DCEP sequence, in terms of mobilizing capacity, toxicity and anti-myeloma activity in comparison with that of the previous VAD-high-dose cyclophosphamide program (group II, 40 patients). RESULTS: In group I 81/106 (76.4%) patients yielded >or= 4x10(6)/kg CD34+ cells, as did 30/40 (75%) in group II but with a significantly higher toxicity in this latter group. In detail, 9 patients in group I (8.5%) had WHO grade III neutropenia versus 35 in group II (87.5%), 5 patients of group I (4.7%) had grade III thrombocytopenia versus 12 patients in group II (30%), and 8 patients in group I (7.5%) experienced an infections fever versus 9 patients in group II (22.5%). Therefore, nearly all patients in group II had to be admitted to hospital (39/40, 97.5%). There was a higher percentage of responses (CR+VGPR+PR) in group I than in group II: 73% versus 50% (p=0.02). INTERPRETATION AND CONCLUSIONS: the VAD-DCEP sequence has an adequate mobilizing capacity, without significant toxicity, and a good anti-myeloma activity, and therefore represents a safe and effective therapeutic approach for multiple myeloma patients at the onset of their disease.

Primary nodal marginal zone B-cell lymphoma: clinical features and prognostic assessment of a rare disease.

This study defined the clinical features and assessed the prognosis of 47 patients (17 males, 30 females, median age 63 years) with primary nodal marginal zone B-cell lymphoma. Forty-five per cent had stage IV disease. Hepatitis C virus serology was positive in 24%. According to the Follicular Lymphoma International Prognostic Index (FLIPI), 33% were classified as low-risk, 34% as intermediate-risk, and 33% as high-risk. The 5-year overall survival (OS) was 69%. In univariate analysis worse OS was associated with: FLIPI (P = 0.02), age > 60 years (P = 0.05) and raised lactate dehydrogenase (P = 0.05). In multivariate analysis, only FLIPI predicted a worse OS (P = 0.02).