Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma

Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2005; 23(4):694-704. DOI: 10.1200/JCO.2005.02.172
Source: PubMed


To evaluate the safety and efficacy of fludarabine plus rituximab in treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma.
This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m2 administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m2/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks.
An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naive and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal.
Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma.

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    • "fludarabine, are powerful therapeutic agents in several lymphoproliferative diseases. Remission of CAD following fludarabine monotherapy has been reported in two patients (Jacobs, 1996; Berentsen et al, 2006), and the fludarabine-rituximab combination has yielded high response rates in WM (Treon et al, 2009) and other low-grade non-Hodgkin lymphoma (Czuczman et al, 2005). "
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    ABSTRACT: Primary chronic cold agglutinin disease (CAD) is a clonal lymphoproliferative disorder accounting for 13-15% of autoimmune haemolytic anaemias. Significant advances have been made in treatment, which was largely unsuccessful until recently. The essential clinical, immunological and pathological features are reviewed, focusing on their relevance for therapy. Non-pharmacological management still seems sufficient in some patients. With the recent improvements, however, drug therapy seems indicated more often than previously thought. Corticosteroids should not be used to treat CAD. Half of the patients respond to rituximab monotherapy; median response duration is 11 months. Fludarabine-rituximab combination therapy is very effective, resulting in 75% response rate, complete remissions in about 20%, and more than 66 months estimated response duration. Toxicity is a concern, and benefits should be carefully weighed against risks. An individualized approach is discussed regarding the choice of fludarabine-rituximab combination versus rituximab monotherapy. Patients requiring treatment should be considered for prospective trials.
    British Journal of Haematology 03/2011; 153(3):309-17. DOI:10.1111/j.1365-2141.2011.08643.x · 4.71 Impact Factor
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    • "Transformation to more aggressive NHL occurs in 15% to 50% of the patients at 5 years.After first relapse patients in otherwise good health are candidate for salvage chemotherapy: combination chemotherapy, immunotherapy, and for some patients with good performance status and responsive disease, myeloablative therapy with stem-cell rescue. A number of cytotoxic agents in combination are active in this patient population and FCR regimen has provided encouraging results as initial or salvage therapy in patients with CLL or indolent NHL [1,2]. Radioimmunotherapy is also an excellent modality in the treatment of NHL; the target antigen, radionuclide emission properties, and chemical stability of radioimmunoconjugates are important factors that contribute to the effectiveness of RIT.90 Yttrium can deliver a high beta energy to tumor (2-3 MeV) and 90 Yttrium Ibritumomab Tiuxetan ( 90 Y -RIT ) - Zevalin® - consists of the anti-CD20 monoclonal antibody ibritumomab (an IgG1k antibody which is the murine parent immunoglobulin to rituximab) covalently bound to the chelating agent tiuxetan and radiolabeled with 90 Yttrium. "
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    ABSTRACT: This retrospective analysis is focused on the efficacy and safety of radioimmunotherapy (RIT) with Zevalin® in nine patients with recurrent follicular lymphoma (FL) who were treated in a consolidation setting after having achieved complete remission or partial remission with FCR. The median age was 63 yrs (range 46-77), all patients were relapsed with histologically confirmed CD20-positive (grade 1 or 2) FL, at relapse they received FCR every 28 days: F (25 mg/m2x 3 days), C (1 gr/m2 day 1) and R (375 mg/m2 day 4) for 4 cycles. Who achieved at least a partial remission, with < 25% bone marrow involvement, was treated with 90Yttrium Ibritumomab Tiuxetan 11.1 or 14.8 MBq/Kg up to a maximum dose 1184 MBq, at 3 months after the completion of FCR. The patients underwent a further restaging at 12 weeks after 90Y-RIT with total body CT scan, FDG-PET/CT and bilateral bone marrow biopsy. Nine patients have completed the treatment: FCR followed by 90Y-RIT (6 patients at 14.8 MBq/Kg, 3 patients at 11.1 MBq/Kg). After FCR 7 patients obtained CR and 2 PR; after 90Y-RIT two patients in PR converted to CR 12 weeks later. With median follow up of 34 months (range 13-50) the current analysis has shown that overall survival (OS) is 89% at 2 years, 76% at 3 years and 61% at 4 years. The most common grade 3 or 4 adverse events were hematologic, one patient developed herpes zoster infection after 8 months following valacyclovir discontinuation; another patient developed fungal infection. Our experience indicate feasibility, tolerability and efficacy of FCR regimen followed by 90Y-RIT in patients relapsed with grades 1 and 2 FL with no unexpected toxicities. A longer follow up and a larger number of patients with relapsed grades 1 and 2 FL are required to determine the impact of this regimen on long-term duration of response and PFS.
    Journal of Experimental & Clinical Cancer Research 02/2011; 30(1):16. DOI:10.1186/1756-9966-30-16 · 4.43 Impact Factor
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    • "This potentiation of granulocytopenia may be related more to an undetermined interaction of rituximab with fludarabine than with bortezomib given the similar myelosuppression between dose levels 5a and 5b. However, it is possible that rituximab may have potentiated bortezomib-related thrombocytopenia, a common toxicity of the proteasome inhibitor that has not been otherwise observed with only fludarabine and rituximab (Czuczman, et al 2005). However, further investigation to validate these observations is needed given the small numbers treated at each dose level. "
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    ABSTRACT: Based on the hypothesis that bortezomib may potentiate fludarabine activity by inhibiting DNA repair, we designed a phase I trial using this combination with rituximab in patients with relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Twenty-four patients were enrolled. Non-Hodgkin lymphoma subtypes included 12 patients with follicular lymphoma, four with marginal zone lymphoma, three with lymphoplasmacytic lymphoma, three with mantle cell lymphoma and two with small lymphocytic/chronic lymphocytic leukaemia. Fludarabine and bortezomib were escalated in cohorts of three patients. Rituximab was added to the maximum tolerated dose of fludarabine and bortezomib and added significant dose-limiting myelosuppression. The maximum tolerated dose was fludarabine 25 mg/m(2) on days 1-3, bortezomib 1.3 mg/m(2) on days 1, 4, 8, 11, with rituximab 375 mg/m(2) on day 1 administered every 21 d. Clinical responses were observed in 11 patients, five of whom were refractory to their most recent treatment regimen. Six additional patients had stable disease for a median of 10 months (range 4-30+). Cumulative myelosuppression and neuropathy was observed. The combination of fludarabine, bortezomib, and rituximab appears to be an active regimen with manageable toxicity for relapsed NHL.
    British Journal of Haematology 07/2009; 147(1):89-96. DOI:10.1111/j.1365-2141.2009.07836.x · 4.71 Impact Factor
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