Predictive Factors for Response to Rituximab in Waldenström's Macroglobulinemia

Dimopoulos, Meletios A.; Anagnostopoulos, Athanasios; Zervas, Constantinos; Kyrtsonis, Marie Christine; Zomas, Athanasios; Bourantas, Constantinos L.; Anagnostopoulos, Nicolaos; Pangalis, Gerrassimos

doi:10.3816/clm.2005.n.014

Cited by 35 publications

(22 citation statements)

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“…The major response rate (CR 1 VGPR 1 PR) was 68% (85% including >MR), which is higher than any of the drugs alone (>PR in 30% to 50% [3][4][5][6][7][15][16][17]27 ), indicating clinical synergism between bortezomib and rituximab. The median time to first response was 3 months, and compares favorably to rituximab alone (median time to response >6 months 3,4,6,7 ).…”

Section: Discussionmentioning

confidence: 99%

“…Rituximab has been widely used for the treatment of WM and has minimal toxicity, but as a monotherapy it is associated with modest response rates. [3][4][5][6] Treatment with rituximab is also associated with a transient increase of serum IgM ("IgM flare") in 30% to 80% of patients 3,7,8 which may exacerbate complications associated with the high levels of paraprotein such as hyperviscosity syndrome. 7,8 Combinations of rituximab with chemotherapy (such as the dexamethasone, rituximab, and cyclophosphamide [DRC] regimen) are associated with better response rates than rituximab alone, however, complete responses are infrequent and median time to response is ;4 months.…”

Section: Introductionmentioning

confidence: 99%

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Primary therapy of Waldenström macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN)

Dimopoulos

García‐Sanz

Gavriatopoulou

et al. 2013

Blood

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177

108

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Key Points• BDR is an active regimen and induces long-lasting responses in patients with newly diagnosed WM.• Induction with single-agent bortezomib may be effective in preventing complications of hyperviscosity or rituximabinduced IgM flare.In this phase 2 multicenter trial, we evaluated the activity of bortezomib, dexamethasone, and rituximab (BDR) combination in previously untreated symptomatic patients with Waldenström macroglobulinemia (WM). To prevent immunoglobulin M (IgM) "flare," single agent bortezomib (1.3 mg/m 2 IV days 1, 4, 8, and 11; 21-day cycle), was followed by weekly IV bortezomib (1.6 mg/m 2 days 1, 8, 15, and 22) every 35 days for 4 additional cycles, followed by IV dexamethasone (40 mg) and IV rituximab (375 mg/m 2 ) in cycles 2 and 5. Fifty-nine patients were treated; 45.5% and 40% were high and intermediate risk per the International Prognostic Scoring System for WM. On intent to treat, 85% responded (3% complete response, 7% very good partial response, 58% partial response [PR]). In 11% of patients, an increase of IgM ‡25% was observed after rituximab; no patient required plasmapheresis. After a minimum follow-up of 32 months, median progression-free survival was 42 months, 3-year duration of response for patients with ‡PR was 70%, and 3-year survival was 81%. Peripheral neuropathy occurred in 46% (grade ‡3 in 7%); only 8% discontinued bortezomib due to neuropathy. BDR is rapidly acting, well tolerated, and nonmyelotoxic, inducing durable responses in previously untreated WM.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Primary therapy of Waldenström macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN)

Dimopoulos

García‐Sanz

Gavriatopoulou

et al. 2013

Blood

Self Cite

177

108

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“…As no significant interaction was observed, the main effects of histology and treatment were then adjusted for prognostic factors. We used the following known prognostic factors of follicular lymphoma international prognostic index (FLIPI), 18 and mantle cell lymphoma international prognostic index (MIPI) 19 and for LPL patients' 4,20 age, ECOG (Eastern Cooperative Oncology Group) performance status, LDH (quotient to upper limit of normal), hemoglobin, white blood cell count, platelet count, number of involved nodal areas and sex.…”

Section: Statisticsmentioning

confidence: 99%

The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG)

et al. 2008

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Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n ¼ 34) or CHOP (n ¼ 30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P ¼ 0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P ¼ 0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P ¼ 0.0033) and in the WM subgroup (P ¼ 0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.

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“…Overall response rates of 44% to 48% were observed in these studies, with median durations of response from 16ϩ to 29ϩ months. 8,9 Among WM patients receiving rituximab as monotherapy, lower response rates have been observed in those patients with high serum IgM (Ͼ 6000 mg/dL) and beta-2 microglobulin (B 2 M; Ͼ 3.0 mg/L) levels, as well as homozygous expression of phenylalanine at amino acid position 158 on CD16 (Fc␥RIIIA-158). [8][9][10] Studies combining rituximab with chemotherapy have also been explored in WM.…”

mentioning

confidence: 99%

“…8,9 Among WM patients receiving rituximab as monotherapy, lower response rates have been observed in those patients with high serum IgM (Ͼ 6000 mg/dL) and beta-2 microglobulin (B 2 M; Ͼ 3.0 mg/L) levels, as well as homozygous expression of phenylalanine at amino acid position 158 on CD16 (Fc␥RIIIA-158). [8][9][10] Studies combining rituximab with chemotherapy have also been explored in WM. 11 The combination of nucleoside analogs plus rituximab has yielded major response rates of 70% to 90%, [12][13][14][15] whereas the combinations of CHOP-R (cyclophosphamide, adriamycin, vincristine, prednisone, rituximab) or DC-R (dexamethasone, cyclophosphamide, rituximab) have resulted in response rates of 80% to 90%.…”

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confidence: 99%

Thalidomide and rituximab in Waldenstrom macroglobulinemia

Treon

Soumerai

Branagan

et al. 2008

Blood

127

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Thalidomide enhances rituximab-mediated, antibody-dependent, cell-mediated cytotoxicity. We therefore conducted a phase 2 study using thalidomide and rituximab in symptomatic Walden-strom macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of daily thalidomide (200 mg for 2 weeks, then 400 mg for 50 weeks) and rituximab (375 mg/m 2 per week) dosed on weeks 2 to 5 and 13 to 16. Twenty-five patients were enrolled, 20 of whom were untreated. Responses were complete response (n 1), partial response (n 15), and major response (n 2), for overall and major response rate of 72% and 64%, respectively, on an intent-to-treat basis. Median serum IgM decreased from 3670 to 1590 mg/dL (P < .001), whereas median hematocrit rose from 33.0% to 37.6% (P .004) at best response. Median time to progression for responders was 38 months. Peripheral neuropathy to thalidomide was the most common adverse event. Among 11 patients experiencing grade 2 or greater neuropathy, 10 resolved to grade 1 or less at a median of 6.7 months. Thalido-mide in combination with rituximab is active and produces long-term responses in WM. Lower doses of thalidomide (ie, < 200 mg/day) should be considered given the high frequency of treatment-related neuropathy in this patient population. This trial is registered at www. clinicaltrials.gov as #NCT00142116. (Blood. 2008;112:4452-4457) Introduction Monoclonal antibodies have been successfully used to treat patients with B-cell malignancies, including Waldenstrom macroglobu-linemia (WM). Most of these efforts have focused on the use of rituximab, a chimeric human IgG 1 monoclonal antibody, which targets CD20, which is widely expressed in WM. 1,2 Studies using standard-dose rituximab therapy have demonstrated activity in WM, with overall response rates of 27% to 35% and median durations of response from 8 to 27 months. 2-7 More recently, the use of extended schedule rituximab has been evaluated wherein patients received 8 infusions of rituximab (375 mg/m 2 per week) at weeks 1 to 4 and 12 to 16. Overall response rates of 44% to 48% were observed in these studies, with median durations of response from 16 to 29 months. 8,9 Among WM patients receiving rituximab as monotherapy, lower response rates have been observed in those patients with high serum IgM (6000 mg/dL) and beta-2 microglobulin (B 2 M; 3.0 mg/L) levels, as well as homozygous expression of phenylalanine at amino acid position 158 on CD16 (FcRIIIA-158). 8-10 Studies combining rituximab with chemotherapy have also been explored in WM. 11 The combination of nucleoside analogs plus rituximab has yielded major response rates of 70% to 90%, 12-15 whereas the combinations of CHOP-R (cyclophosphamide, adria-mycin, vincristine, prednisone, rituximab) or DC-R (dexametha-sone, cyclophosphamide, rituximab) have resulted in response rates of 80% to 90%. 16-18 Median time to progression (TTP) in excess of 3 years has been reported with these combinations. Although these combinations have produced more impressive responses, greater toxi...

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Predictive Factors for Response to Rituximab in Waldenström's Macroglobulinemia

Cited by 35 publications

References 10 publications

Primary therapy of Waldenström macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN)

Primary therapy of Waldenström macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN)

The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG)

Thalidomide and rituximab in Waldenstrom macroglobulinemia

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