Phase II Trial of Weekly Bortezomib in Combination With Rituximab in Relapsed or Relapsed and Refractory Waldenström Macroglobulinemia

Ghobrial, Irène M.; Hong, Fangxin; Padmanabhan, Swaminathan; Badros, Ashraf; Rourke, Meghan; Leduc, Renee; Chuma, Stacey; Kunsman, Janet; Warren, Diane; Harris, Brianna; Sam, Amy; Anderson, Kenneth C.; Richardson, Paul G.; Treon, Steven P.; Weller, Edie; Matous, Jeffrey

doi:10.1200/jco.2009.25.3237

Cited by 146 publications

(74 citation statements)

References 31 publications

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“…The responses were sustainable, with long PFS and DOR, suggesting that RFC is a very effective regimen for relapsed/refractory patients. In Tedeschi's study and in ours, the PFS among relapsed patients treated with RFC was the longest ever reported [4,18,19]. Furthermore, we observed a late improvement of the responses in 25 patients.…”

Section: Discussionsupporting

confidence: 57%

Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

et al. 2016

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Waldenstrom's macroglobulinemia is generally treated with alkylating agents, purine analogs and monoclonal antibodies, alone or in combination. We report the outcomes of 82 patients (median age 61 years) treated with the RFC combination. Twenty-five patients were treatment-naive. RFC was administered every 4 weeks, for a median of five cycles. At treatment discontinuation, the overall response rate was 85.4%. The responses improved after treatment discontinuation in 25 patients, with a median time to best response achievement of 10.8 months, raising the major response rate (PR, VGPR and CR) from 64.6% to 76.8%. With a median follow-up of 47 months, the median progression-free survival time had not been reached (67% PFS at 48 months) and was influenced by age and treatment status before RFC. Likewise, the median time to next therapy had not been reached. Two cases of myelodysplastic syndrome/AML and 3 cases of transformation to aggressive lymphoma occurred. Thirteen patients died. The 3-year overall survival rate was 90%. Long-lasting cytopenias occurred in 19 patients. The RFC combination thus gave a high response rate and durable responses, even in heavily treatment-experienced patients. The high incidence of long-lasting cytopenia might be reduced by giving fewer courses and thereby minimizing myelotoxicity. Waldenstrom's macroglobulinemia (WM) is a rare B-cell malignancy characterized by the production of a monoclonal immunoglobulin (IgM) by welldifferentiated plasmacytic lymphocytes. Therapy is currently reserved for patients with constitutional symptoms, bone marrow or peripheral lymphoid organ involvement, and complications due to the monoclonal IgM component [1]. There is no consensus treatment strategy, and most clinical trials in WM have so far consisted of small phase II studies with widely differing inclusion and response criteria. Classically used chemotherapeutic agents consist of alkylating agents (chlorambucil, cyclophosphamide), purine analogues (fludarabine, 2-chlorodeoxyadenosine or 2CDA), a proteasome inhibitor (bortezomib) and bendamustine, used either alone or, more often, combined with immunotherapy (principally rituximab). A combination of cyclophosphamide and purine analogues offers synergistic activity, as DNA breaks caused by cyclophosphamide cannot be repaired in the presence of a purine analogue [2]. Studies of the cyclophosphamide and fludarabine combination in WM patients showed an overall response rate (ORR) of 55-77%, and a median time to treatment failure of around 24 months [3]. The fludarabine and rituximab combination has also been studied in a phase II trial, with an ORR of 95.3%, a 4-year progression-free survival rate (PFS) of 67%, and a median time to progression (TTP) of 77 months [4]. Rituximab, fludarabine, and cyclophosphamide combination therapy (RFC) yields a high response rate in patients with chronic lymphocytic leukemia (CLL), both as first-line treatment and after relapse [5,6], and is more effective than the FC combination in untreated CLL patients [7]. Until no...

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Section: Discussionsupporting

confidence: 57%

Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

et al. 2016

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“…Weekly dosing [28][29][30] and subcutaneous administration may reduce rates and severity of neuropathy and is explored in a clinical trial (NCT01592981). Bortezomib is not stem cell toxic, and longterm follow-up in myeloma patients does not suggest a risk for secondary malignancies.…”

Section: Bortezomibmentioning

confidence: 99%

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus

Dimopoulos

Kastritis

Owen

et al. 2014

Blood

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140

134

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Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

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“…Given that neuropathy is a major toxicity in patients receiving standard treatment schedules of bortezomib, we and others have developed studies using bortezomib once a week at 1.6 mg/m 2 in an attempt to reduce the occurrence of peripheral neuropathy 47 . Several clinical trials are ongoing using weekly bortezomib in combination with rituximab in newly diagnosed or in relapsed WM 48,49 . The results of the study using weekly bortezomib and rituximab without the addition of dexamethasone in patients with relapsed WM has been recently presented 48 .…”

Section: Novel Therapeutic Agentsmentioning

confidence: 99%

“…Several clinical trials are ongoing using weekly bortezomib in combination with rituximab in newly diagnosed or in relapsed WM 48,49 . The results of the study using weekly bortezomib and rituximab without the addition of dexamethasone in patients with relapsed WM has been recently presented 48 . All patients received bortezomib IV weekly at 1.6 mg/ m 2 on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m 2 weekly on cycles 1 and 4.…”

Section: Novel Therapeutic Agentsmentioning

confidence: 99%

New therapeutic approaches for Waldenstrom macroglobulinemia

Stedman¹,

Roccaro²,

Leleu³

et al. 2010

Drugs Fut

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Waldenstrom Macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lymphoplasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum. WM is an incurable disease, with an overall medial survival of only 5-6 years. First-line therapy of WM has been based on single-agent or combination therapy with alkylator agents (e.g. chlorambucil or cyclophasphamide), nucleoside analogues (cladribine or fludarabine), and the monoclonal antibody rituximab. Novel therapeutic agents that have demonstrated efficacy in WM include thalidomide, lenalidomide, bortezomib, everolimus, Atacicept, and perifosine. The range of the ORR to these agents is between 25-80%. Ongoing and planned future clinical trials include those using PKC inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as panobinostat, humanized CD20 antibodies such as Ofatumumab, and additional alkylating agents such as bendamustine. These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM.

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Phase II Trial of Weekly Bortezomib in Combination With Rituximab in Relapsed or Relapsed and Refractory Waldenström Macroglobulinemia

Abstract: The combination of weekly bortezomib and rituximab showed significant activity and minimal neurologic toxicity in patients with relapsed WM.

Cited by 146 publications

References 31 publications

Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

Efficacy and long‐term toxicity of the rituximab‐fludarabine‐cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia

Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus

New therapeutic approaches for Waldenstrom macroglobulinemia

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