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

ABSTRACT 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 · 4.96 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 · 4.96 Impact Factor
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    • "Of particular concern, however, was the occurrence in this study of delayed neutropenia several months after completion of therapy, which led directly to two infectious deaths. Although grade 3–4 neutropenia is commonly seen during therapy, neutropenia occurring outside the usual post-therapy window but earlier than expected for secondary myelodysplasia has not been reported in prior studies of FR (Byrd, et al 2003, Czuczman, et al 2005, Savage, et al 2003, Schulz, et al 2002) or in long-term follow-up studies of the rate of secondary myelodysplasia and AML (Cheson, et al 1999b, McLaughlin, et al 2005, Morrison, et al 2002). Both of these patients had aplastic bone marrow affecting all lineages but without evidence of cytogenetic abnormalities associated with MDS. "
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    ABSTRACT: The marginal zone lymphomas (MZLs) are a recently defined group of related diseases that probably arise from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric mucosa-associated lymphoid tissue (MALT) lymphoma has been largely limited to retrospective case series. This prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas enrolled 26 patients, 14 with nodal MZL, eight with MALT lymphomas and four with splenic MZL; 81% were receiving initial systemic therapy. Only 58% [95% confidence interval (CI) 37-77%] of patients completed the planned six cycles, due to significant haematological, infectious and allergic toxicity. Four late toxic deaths occurred due to infections [15% (95% CI 4.3-35%)], two related to delayed bone marrow aplasia and two related to myelodysplastic syndrome. Nonetheless, the overall response rate was 85% (95% CI 65-96%), with 54% complete responses. The progression-free survival at 3.1 years of follow-up is 79.5% (95% CI 63-96%). We conclude that, although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of MZLs, the significant haematological and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study MZLs as a separate entity.
    British Journal of Haematology 04/2009; 145(6):741-8. DOI:10.1111/j.1365-2141.2009.07677.x · 4.96 Impact Factor
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