Originally published as JCO Early Release 10.1200/JCO.2007.10.9926 on June 18 2007

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Primary Treatment of Waldenström Macroglobulinemia With Dexamethasone, Rituximab, and Cyclophosphamide

Meletios Athanasios Dimopoulos, Athanasios Anagnostopoulos, Marie-Christine Kyrtsonis, Konstantinos Zervas, Constantinos Tsatalas, Garyfallia Kokkinis, Panagiotis Repoussis, Argyris Symeonidis, Souzana Delimpasi, Eirini Katodritou, Elina Vervessou, Evridiki Michali, Anastasia Pouli, Dimitra Gika, Amalia Vassou, Evangelos Terpos, Nikolaos Anagnostopoulos, Theophanis Economopoulos, Gerasimos Pangalis

From the Departments of Clinical Therapeutics, Internal Medicine, and the Second Department of Propedeutic Medicine, University of Athens School of Medicine; Department of Hematology, Sismanoglion Hospital; Department of Hematology, Metaxa Hospital; Department of Hematology, Evangelismos Hospital; Department of Hematology, Erikos Dynan Hospital; Department of Hematology, Genimata General Hospital; Department of Hematology, General Airforce Hospital, Athens; Department of Hematology, Theagenion Cancer Center, Thessaloniki; Department of Hematology, University of Alexandroupolis; Department of Hematology, University of Patras; Department of Hematology, Agios Savvas Cancer Center; and the Department of Hematology, University of Ioannina, Greece

Address reprint requests to Meletios A. Dimopoulos, MD, Department of Clinical Therapeutics, Alexandra Hospital, 80 Vass Sofias, Athens 11528, Greece; e-mail: meldimop{at}hotmail.com

	ABSTRACT

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Purpose: Alkylating agents and the anti-CD20 monoclonal antibody rituximab are among appropriate choices for the primary treatment of symptomatic patients with Waldenström macroglobulinemia (WM), and they induce at least a partial response in 30% to 50% of patients. To improve these results, we designed a phase II study that included previously untreated symptomatic patients with WM who received a combination of dexamethasone, rituximab, and cyclophosphamide (DRC).

Patients and Methods: Seventy-two patients were treated with dexamethasone 20 mg intravenously followed by rituximab 375 mg/m² intravenously on day 1 and cyclophosphamide 100 mg/m² orally bid on days 1 to 5 (total dose, 1,000 mg/m²). This regimen was repeated every 21 days for 6 months. Patients' median age was 69 years and many had features of advanced disease such as anemia (57%), hypoalbuminemia (40%), and elevated serum beta₂-microglobulin (43%).

Results: On an intent-to-treat basis, 83% of patients (95% CI, 73% to 91%) achieved a response, including 7% complete, 67% partial, and 9% minor responses. The median time to response was 4.1 months. The 2-year progression-free survival rate for all patients was 67%; for patients who responded to DRC, it was 80%. The 2-year disease-specific survival rate was 90%. Treatment with DRC was well tolerated, with 9% of patients experiencing grade 3 or 4 neutropenia and approximately 20% of patients experiencing some form of toxicity related to rituximab.

Conclusion: Our large, multicenter trial showed that the non–stem-cell toxic DRC regimen is an active, well-tolerated treatment for symptomatic patients with WM.

	INTRODUCTION

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Waldenström macroglobulinemia (WM) is a distinct clinicopathologic entity confined to patients with lymphoplasmacytoid lymphoma, which involves the bone marrow and causes the secretion of a monoclonal immunoglobulin M (IgM) into the serum.¹ Some patients who fulfill the diagnostic criteria of WM are diagnosed by chance and have no symptoms or signs attributable to the underlying lymphoma or to the monoclonal IgM. Such patients with asymptomatic WM should be recognized at diagnosis and should not be treated because they may remain stable for several years.^2,3 Most patients with the diagnosis of WM have symptoms attributable to tumor infiltration and/or monoclonal IgM. These patients require treatment to control symptoms and reverse or prevent complications of the disease. Several chemotherapeutic agents and regimens have been administered to patients with WM. Given the rarity of this disease, the different diagnostic and response criteria, and the small size of most trials, it has been difficult to select the most active treatment.⁴ During the Second International Workshop on Waldenstrom's Macroglobulinemia, which was held September 2002 in Athens, Greece, a Consensus Panel of Experts recommended that single-agent therapy with alkylating agents, nucleoside analogs, and the monoclonal antibody rituximab were reasonable choices for the first-line treatment of WM.⁵ In formulating its recommendation, the panel recognized the paucity of randomized trials in WM and concluded that it was not possible to recommend the use of one first-line agent over another. The panel emphasized that individual patient considerations should be taken into account in selecting a first-line agent, including the presence of cytopenias, need for rapid disease control, age, and candidacy for autologous stem-cell transplantation therapy. Furthermore, a recommendation was made that for patients who may be eligible for autologous transplantation, exposure to alkylating agents and nucleoside analogs should be limited in view of reports suggesting depletion of stem cells by these agents.⁵ Finally, clear indications for treatment initiation and strict response criteria were also defined.^6,7

On the basis of the above facts, we designed a multicenter, prospective trial that included previously untreated patients with clearly defined indications for treatment initiation. We wanted to develop a stem-cell–sparing regimen that will combine active agents against WM with minimal myelosuppression and immunosuppression. Thus the combination of dexamethasone, rituximab, and cyclophosphamide (DRC) was designed.

	PATIENTS AND METHODS

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Between November 2002 and April 2006, 72 patients with WM were enrolled onto this multicenter trial after informed consent was obtained according to institutional guidelines. The diagnosis of WM was established by the presence of lymphoplasmacytoid lymphoma involving the bone marrow and by the detection of serum monoclonal IgM.¹ All patients were required to have CD20⁺ tumor cells, which was determined by either bone marrow immunohistochemistry or flow cytometry. In addition, at least one of the following criteria for initiation of treatment was required: "B" symptoms, bulky (> 5 cm) and/or symptomatic lymphadenopathy, symptomatic splenomegaly or hepatomegaly, hyperviscosity syndrome, symptomatic peripheral neuropathy, symptomatic cryoglobulinemia, symptomatic cold agglutinin anemia, hemoglobin less than 10 g/dL, or platelet count less than 100 x 10⁶/dL.

The DRC regimen consisted of dexamethasone 20 mg intravenously followed by rituximab 375 mg/m² intravenously on day 1. Rituximab was mixed with normal saline at a final concentration of no more than 1 to 4 mg/mL and was administered as described previously.⁸ Furthermore, oral cyclophosphamide 100 mg/m² bid was administered on days 1 to 5 (total dose, 1,000 mg/m²). DRC courses were repeated every 21 days for six courses, and then patients without progressive disease were observed without treatment.

All patients underwent baseline evaluations that included detailed physical examination, blood counts, hepatic and renal function tests, serum protein electrophoresis, quantitation of serum immunoglobulins and serum beta₂-microglobulin (ß₂-microglobulin). These tests were repeated before each course of DRC, 3 weeks after completion of DRC, and every 3 months thereafter. Bone marrow aspiration and/or biopsy, chest x-ray, and computed tomography of the abdomen and pelvis were performed at baseline and were repeated when indicated to confirm response or progression.

All patients who received at least 1 day of DRC were eligible for assessment of toxicity and response. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTC). Patients who discontinued treatment before a response could be assessed were rated as having progressive disease. Thus, the results were evaluated on an intention-to-treat basis. Measurements of serum protein were made from serum protein electrophoresis. Complete response (CR) was defined as complete disappearance of disease at all involved sites and negative serum immunofixation. Partial response (PR) was defined as a greater than 50% reduction of serum monoclonal protein concentration along with more than 50% reduction of tumor infiltrate at all involved sites and resolution of symptoms attributable to WM. Minor response (MR) was categorized by 25% but less than 50% reduction of serum monoclonal IgM determined by protein electrophoresis and no new symptoms or signs of active disease. Stable disease was categorized by less than 25% reduction and less than 25% increase of serum monoclonal IgM without progression of adenopathy, organomegaly, cytopenias, or clinically significant symptoms caused by disease and/or signs of WM. Patients were rated as having progressive disease when they did not meet criteria for response or stable disease. Progression was defined by at least a 25% increase of serum monoclonal protein from the lowest value or worsening of cytopenias, lymphadenopathy, or organomegaly, or appearance of disease-related complications.^7,9 Differences in the response rate between groups of patients were tested for statistical significance using Fisher's exact test.

Time to progression was defined as the time from start of treatment with DRC to disease progression. Time to next treatment was defined as the time from start of treatment with DRC to start of second-line treatment. This variable was calculated because some patients with WM who fulfill the criteria for progression may not need additional treatment for various periods of time. Cause of death was defined as death as a result of disease or complications of treatment, or as death unrelated to WM, such as cardiac, pulmonary, or cerebrovascular diseases, or nonhematologic malignancies. For disease-specific survival, deaths unrelated to WM were censored. Time to progression, time to next treatment, disease-specific survival, and overall survival were calculated according to the Kaplan-Meier method, and differences in the curves were tested for statistical significance using the log-rank test.

	RESULTS

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Patients and Disease Characteristics
Patient characteristics are listed in Table 1. The patients' median age was 69 years (range, 33 to 89 years). The median level of serum monoclonal protein was 3.6 g/dL (range, 0.3 to 11.7 g/dL). The serum light-chain type was kappa in 78% of patients and lambda in 22%. Many patients had features of advanced disease and several patients had adverse prognostic factors such as advanced age, anemia, elevated serum ß₂-microglobulin. The primary reasons for initiating treatment were anemia (32 patients); symptoms and signs of hyperviscosity (17 patients); significant splenomegaly or lymphadenopathy (10 patients); weight loss, night sweats, or fever (six patients); peripheral neuropathy (two patients); cold agglutinin anemia (two patients); cryoglobulinemia (one patient); lung involvement (one patient); and pleural involvement (one patient).

On an intent-to-treat basis, the overall response rate was 83% (95% CI, 73% to 91%) including 7% CRs, 67% PRs, and 9% MRs. Furthermore, six patients (8%) were rated as having stable disease and six patients (8%) were rated as having progressive disease. Median time to 50% reduction of serum monoclonal protein was 4.1 months (range, 0.7 to 14 months).

Thirty-two percent of patients experienced an increase in serum monoclonal protein levels between baseline and the first scheduled postbaseline point, which was on day 21 (ie, the day of the second course of DRC). This increase was usually minor, with a 25% increase occurring in 11% of patients. In 88% of patients with an IgM flare, the final serum monoclonal protein level after completion of DRC treatment was lower than baseline level, and 83% achieved at least an MR. Respectively, 94% of the patients without an IgM flare achieved at least MR. When the same analysis was restricted to patients who achieved CR or PR after DRC, we observed that 26% of such patients experienced an IgM flare, and that in 9% of patients the IgM increase was 25% from baseline. The IgM flare did not have clinical consequences such as triggering symptoms or signs of hyperviscosity in any patient.

Several variables were analyzed for their possible association with response, such as age; sex; presence of "B" symptoms; lymphadenopathy; splenomegaly; hemoglobin; immunoglobulin light-chain type; levels of serum monoclonal protein, albumin, and ß₂-microglobulin levels; and degree of bone marrow infiltration. Only the presence of B symptoms was associated with a trend for lower response rate (79% v 59%; P = .09). Among 17 patients who started DRC treatment because of symptoms and signs of elevated serum viscosity, 12 patients (71% achieved at least a PR) responded.

Time to Progression and Survival
With a median follow-up of 23.4 months, the 2-year progression-free survival rate for all patients was 67% and 80% for patients who responded to DRC (Fig 1). Multiple variables were assessed for their possible correlation with time to progression. The presence of lymphadenopathy was associated with shorter time to progression (P = .02). The 2-year survival without additional treatment was 78%. Five patients met the criteria for progression but had not yet required re-treatment because of the absence of clinically significant symptoms and signs attributable to WM.⁹

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Time to progression for (A) all patients and (B) for those who responded to dexamethasone, rituximab, and cyclophosphamide.

Toxicity
Toxicity encountered during treatment with DRC is summarized in Table 2. Only seven patients developed grade 3 or 4 neutropenia; thrombocytopenia was virtually absent. Adverse effects related to the infusion of rituximab such as chills, fever, and headache were usually mild, of brief duration, readily reversible after reduction of the infusion rate, and occurred with the first infusion of rituximab. However, in two patients, severe hypotension was noted during the first infusion of rituximab and in one patient the DRC treatment was discontinued. One patient developed febrile interstitial pneumonia associated with severe hypoxia 2 weeks after the initiation of DRC. The etiology of this complication was not determined and the patient died despite treatment with a broad-spectrum antibiotic, cotrimoxazole, and ganciclovir. Twenty infectious episodes were documented during treatment. One episode caused the patient's death (NCI CTC grade 5). Nine patients required hospitalization and intravenous antibiotics for treatment of neutropenic fever (four patients) or pneumonia (five patients; NCI CTC grade 3), and 10 episodes consisting of upper respiratory tract infection (six patients), urinary tract infection (two patients), and herpes zoster (two patients) were treated on an outpatient basis (NCI CTC grade 2).

	DISCUSSION

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The combination of DRC was designed in 2002 on the basis of data available at that time: there was evidence that rituximab is a nonmyelosuppressive agent that is not toxic to stem cells, with activity in approximately one third of previously untreated patients with WM.^8,10,11 Rose et al¹² had reported in vitro data indicating that the addition of dexamethasone to rituximab resulted in supra-additive cytotoxicity with respect to its direct antiproliferative and apoptotic effects, and induced a cell-dependent increased sensitivity to rituximab-induced complement-dependent cytotoxicity. Older series had indicated that the alkylating agent cyclophosphamide, either alone or with vincristine and prednisone, had activity in WM.^13,14 Furthermore, cyclophosphamide is well tolerated, induces minimal myelosuppression, does not deplete marrow stem cells, and is not associated with increased risk for myelodysplasia and secondary leukemia. Finally, Mohammad et al¹⁵ had reported that the combination of DRC induced cures in the Wayne State University-WM xenograft model and a PR in a patient with resistant WM.

We administered the DRC combination to a large number of patients with WM who had a clear indication to start treatment, and we applied strict criteria to assess response based on the recommendations of the Second International Workshop on Waldenstrom's Macroglobulinemia, which was held in 2002.^6,7 We documented responses in 83% of patients, including immunofixation-negative CRs in 7% of patients. This response rate appears higher than that observed with single-agent rituximab, indicating that there may be in vivo synergism of this combination. As is the case with single-agent rituximab, the time to response after DRC was slow, indicating that for patients who need rapid disease control, combinations of rituximab with nucleoside analogs or with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) may be more appropriate.^16-18 The range of median times required for a 50% reduction in the serum monoclonal protein was very wide. This observation is consistent with prior studies with single-agent rituximab.⁹ Physicians should be aware of this and should repeat electrophoretic studies several months after completion of treatment to detect patients with delayed responses. Conversely, the myelotoxicity of DRC was minimal, indicating that this combination may be attractive for patients whose primary indication for treatment is cytopenia(s). Moreover, doxorubicin may be potentially harmful in this older patient population. Furthermore, the infectious complications after DRC were not as pronounced as those observed after the administration of combinations that include rituximab and nucleoside analogs.^18,19

A recent report indicated that patients with low grade lymphomas treated with fludarabine and rituximab had a 70% cumulative probability to develop a non-neutropenic infection at 3 years.²⁰ Several studies have assessed the activity of rituximab-based therapy in patients with WM. Weber et al¹⁶ have administered the combination of cladribine, cyclophosphamide, and rituximab to 17 previously untreated patients with WM and noted a 94% objective response rate, including 18% CRs. Buske et al²¹ randomly assigned 72 newly diagnosed patients with lymphoplasmacytoid lymphoma and WM to CHOP with or without rituximab. The objective response rate was 94% for rituximab plus CHOP (R-CHOP; 11% CRs) versus 69% for CHOP (4% CRs; P = .012). Furthermore, there was significant prolongation of the time to treatment failure for the patients treated with R-CHOP.²¹ Treon et al¹⁹ treated 43 patients with WM, most of whom were treatment-naïve, with the combination of fludarabine and rituximab. An objective response rate was noted in 90.1% of patients, including 7% CRs. These rituximab-based regimens, including our regimen, indicate significant overall efficacy but had a relatively low CR rate.

To our knowledge, we were the first to describe a transient increase of monoclonal protein after administration of single-agent rituximab.⁸ Subsequent and more detailed studies have indicated that this initial IgM flare may occur in 54% to 90% of patients.^22,23 We saw the same effect after DRC but at a lower incidence of 32%; only 11% of patients experienced a 25% IgM increase. The concomitant administration of cyclophosphamide may explain the lower incidence of an IgM flare. However, in patients who present with high levels of serum monoclonal IgM, pheresis may be considered before the administration of rituximab-based therapies.

High-dose therapy with autologous stem-cell transplantation has been applied with success in several patients with advanced and refractory WM.^24-27 However, it has been difficult to identify at diagnosis subsets of patients who may benefit from this procedure. A recently proposed International Prognostic Scoring System for Waldenstrom's Macroglobulinemia had identified a subset of patients with an adverse prognosis and a median survival of about 3 years.²⁸ Such patients are suitable for treatment strategies that may incorporate high-dose therapy. After our DRC regimen, we were able to collect stem cells in all patients in whom this procedure was applied.

With a median follow-up of approximately 2 years, 80% of responding patients remain free of progression. The 2-year progression-free survival for all patients was 67%, but because several patients who had met criteria for progression have not required subsequent treatment yet, the 2-year survival without additional treatment was 78%. The 2-year overall survival was 81% but the 2-year cause-specific survival was 90%. These data confirm a recent report from the Mayo Clinic (Rochester, MN), which indicated that in a large series of patients with WM the median overall survival was 6.4 years, whereas the disease-specific survival was 11.2 years.²⁹ Thus, we believe that it is important to document prospectively the cause of death in WM trials.

We conclude that the DRC regimen is well tolerated, easily administered, convenient, and active for symptomatic patients with previously untreated WM. Our data provide additional support to the recent recommendation that combinations of rituximab with nucleoside analogs, with alkylating agents, or with CHOP may be appropriate choices for the first-line treatment of WM.³⁰

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Meletios Athanasios Dimopoulos, Roche Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Meletios Athanasios Dimopoulos, Athanasios Anagnostopoulos, Marie-Christine Kyrtsonis, Konstantinos Zervas, Constantinos Tsatalas, Garyfallia Kokkinis, Panagiotis Repoussis, Argyris Symeonidis, Souzana Delimpasi, Eirini Katodritou, Elina Vervessou, Evridiki Michali, Anastasia Pouli, Amalia Vassou, Evangelos Terpos, Nikolaos Anagnostopoulos, Theophanis Economopoulos, Gerasimos Pangalis

Administrative support: Meletios Athanasios Dimopoulos, Athanasios Anagnostopoulos, Dimitra Gika

Provision of study materials or patients: Meletios Athanasios Dimopoulos, Marie-Christine Kyrtsonis, Konstantinos Zervas, Constantinos Tsatalas, Garyfallia Kokkinis, Argyris Symeonidis, Evridiki Michali, Anastasia Pouli, Amalia Vassou, Evangelos Terpos

Collection and assembly of data: Meletios Athanasios Dimopoulos, Athanasios Anagnostopoulos, Marie-Christine Kyrtsonis, Konstantinos Zervas, Constantinos Tsatalas, Garyfallia Kokkinis, Panagiotis Repoussis, Argyris Symeonidis, Souzana Delimpasi, Eirini Katodritou, Elina Vervessou, Evridiki Michali, Anastasia Pouli, Dimitra Gika, Amalia Vassou, Evangelos Terpos, Nikolaos Anagnostopoulos, Theophanis Economopoulos, Gerasimos Pangalis

Data analysis and interpretation: Meletios Athanasios Dimopoulos, Athanasios Anagnostopoulos, Marie-Christine Kyrtsonis, Konstantinos Zervas, Constantinos Tsatalas, Garyfallia Kokkinis, Panagiotis Repoussis, Argyris Symeonidis, Souzana Delimpasi, Eirini Katodritou, Elina Vervessou, Evridiki Michali, Anastasia Pouli, Dimitra Gika, Amalia Vassou, Evangelos Terpos, Nikolaos Anagnostopoulos, Theophanis Economopoulos, Gerasimos Pangalis

Manuscript writing: Meletios Athanasios Dimopoulos, Athanasios Anagnostopoulos, Marie-Christine Kyrtsonis, Konstantinos Zervas, Constantinos Tsatalas, Garyfallia Kokkinis, Panagiotis Repoussis, Argyris Symeonidis, Souzana Delimpasi, Eirini Katodritou, Elina Vervessou, Evridiki Michali, Anastasia Pouli, Amalia Vassou, Evangelos Terpos, Nikolaos Anagnostopoulos, Theophanis Economopoulos, Gerasimos Pangalis

Final approval of manuscript: Meletios Athanasios Dimopoulos, Athanasios Anagnostopoulos, Marie-Christine Kyrtsonis, Konstantinos Zervas, Constantinos Tsatalas, Garyfallia Kokkinis, Panagiotis Repoussis, Argyris Symeonidis, Souzana Delimpasi, Eirini Katodritou, Elina Vervessou, Evridiki Michali, Anastasia Pouli, Dimitra Gika, Amalia Vassou, Evangelos Terpos, Nikolaos Anagnostopoulos, Theophanis Economopoulos, Gerasimos Pangalis

	NOTES

 
published online ahead of print at www.jco.org on June 18, 2007.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted January 26, 2007; accepted May 1, 2007.

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