WALDENSTROM S macroglobulinemia (WM) is a

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1 Treatment of Waldenstrom s Macroglobulinemia With Thalidomide By Meletios A. Dimopoulos, Athanassios Zomas, Nora A. Viniou, Vassiliki Grigoraki, Eleni Galani, Charis Matsouka, Olga Economou, Nikolaos Anagnostopoulos, and Panayiotis Panayiotidis WALDENSTROM S macroglobulinemia (WM) is a low-grade lymphoplasmacytoid lymphoma that produces a monoclonal immunoglobulin M (IgM). The disease usually affects older persons and may cause symptoms as a result of anemia, lymphadenopathy, splenomegaly, elevated serum viscosity, or a combination of these. Plasmapheresis, which reduces the amount of circulating IgM, and chemotherapy, which inhibits tumor growth, have been the standard therapy for symptomatic macroglobulinemia. 1,2 Active chemotherapeutic agents include alkylating agents, especially chlorambucil and nucleoside analogs such as fludarabine and cladribine. Objective responses occur in 50% to 70% of previously untreated patients, with a subsequent median survival of about 5 years. 3,4 Despite long-term disease control in some patients, all patients eventually develop resistance to the above treatments. Limited trials with high-dose therapy and autologous stem-cell transplantation and with rituximab, a chimeric anti-cd20 monoclonal antibody, have shown activity in some patients with chemoresistant disease. 5,6 However, investigation of new treatments is warranted. From the Departments of Clinical Therapeutics and Internal Medicine, University of Athens School of Medicine; and Department of Hematology, Genimatas General Hospital, Athens, Greece. Submitted September 28, 2000; accepted May 8, Address reprint requests to Meletios A. Dimopoulos, MD, 227 Kifissias Ave, Kifissia, Athens 14561, Greece; mdimop@med.uoa.gr by American Society of Clinical Oncology X/01/ /$20.00 Purpose: We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom s macroglobulinemia (WM). Patients and Methods: Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. Results: On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. Conclusion: Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant. J Clin Oncol 19: by American Society of Clinical Oncology. Recently, thalidomide, an oral agent with immunomodulatory and antiangiogenetic properties, has shown activity in approximately 30% of patients with refractory multiple myeloma. 7 Based on these encouraging data, we performed a phase II study to assess the activity of thalidomide in patients with WM requiring treatment. PATIENTS AND METHODS Between July 1999 and April 2000, 20 patients with WM were treated with thalidomide after informed consent was obtained according to institutional guidelines. Patient characteristics are listed in Table 1. The median age was 74 years (range, 48 to 85 years), four patients were older than 80 years, and 11 were male. The median serum monoclonal protein concentration was 29.5 g/l (range, 5 to 70 g/l). Five patients had hemoglobin less than 100 g/l at study entry, and three additional patients with higher hemoglobin values were receiving erythropoietin. The primary reasons for initiating treatment were worsening anemia (five patients), significant splenomegaly (four patients), weight loss, night sweats, fever or pruritus (four patients), hyperviscosity syndrome (four patients), lymphadenopathy (two patients), and thrombocytopenia (one patient). Among the 10 previously treated patients, four had not responded to any previous regimen (primary refractory), five patients were relapsing despite chemotherapy (resistant relapse), and one patient was relapsing while being followed without treatment. All previously treated patients had received alkylating agent based regimens. Furthermore, three patients were resistant to fludarabine-containing treatments and one to pentostatin. All patients underwent baseline evaluations that included detailed physical examination, blood counts, hepatic and renal function tests, bone marrow aspirate and/or biopsy, serum and urine protein electrophoreses, quantitation of serum immunoglobulins, serum lactate dehydrogenase and B2-microglobulin. Chest x-ray and computed tomography of the abdomen and pelvis were also performed. For the first 2 months of treatment, patients were followed up with biweekly physical examinations, blood counts, renal and liver function tests, and serum 3596 Journal of Clinical Oncology, Vol 19, No 16 (August 15), 2001: pp

2 THALIDOMIDE FOR MACROGLOBULINEMIA Table 1. Patient Characteristics and urine electrophoretic studies. Thereafter, these tests were repeated on a monthly basis. Repeat imaging procedures and bone marrow assessment were performed when monoclonal protein reached maximum reduction. Three patients were receiving erythropoietin when registered in the study. This agent was discontinued and no patient received erythropoietin while on study. The initial dose of thalidomide was 200 mg orally (PO) daily at bedtime with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients who received thalidomide for at least 1 day were eligible for assessment of toxicity and response. Toxicity was graded according to the classification system of the World Health Organization. 8 Patients who discontinued treatment before a response could be assessed were considered to have had no response to thalidomide. Thus, the results were evaluated on an intent-to-treat basis. Responses were evaluated as previously defined. 9 Measurements of monoclonal protein were made from serum protein electrophoresis. Complete response was defined as disappearance of the monoclonal protein by immunofixation, resolution of lymphadenopathy and of hepatosplenomegaly, and less than 20% lymphocytes in the bone marrow. Partial response was defined as a greater than 50% reduction of serum monoclonal protein concentration for at least 2 months; responding patients were also required to achieve more than 50% reduction of tumor infiltrate at all involved sites. For the purpose of this study, minor response was defined as at least 25% reduction of serum monoclonal protein; and the disease was considered stable when the serum monoclonal protein changes were less than 25% without evidence of additional complications of the macroglobulinemia. Patients were considered in progression when they did not meet criteria for response or stable disease. Relapse was defined by at least a 25% increase of monoclonal protein from the lowest value or reappearance of lymphadenopathy, hepatosplenomegaly, or anemia. Patients follow-up was updated in January RESULTS No. of Patients (N 20) % Age 70 years Disease status Previously untreated Pretreated Lymphadenopathy Splenomegaly 7 35 Hepatomegaly 3 15 Hemoglobin 100 g/l 5 25 Platelets /L 3 15 Serum peak 40 g/l 6 30 Bence Jones protein 500 mg/24 h 3 15 Light chain Kappa Lambda 4 20 B2-microglobulin 4.0 mg/l 7 35 Bone marrow lymphocytes 50% Response Five (25%) of 20 patients achieved a partial response after treatment with thalidomide including one patient with Table 2. Response According to Disease Status and Duration of Prior Treatment Disease Status No. of Patients No. of Responses Untreated 10 3 Primary refractory 4 2 Relapse off treatment 1 0 Resistant relapse 5 0 Prior treatment 24 months months more than 75% reduction of serum monoclonal protein. Five patients were rated as stable disease with a subsequent median time to progression of 4 months (range, 3 to 8 months). Ten patients experienced early disease progression. All responding patients were female. Responses occurred in three of 10 previously untreated patients and in two of 10 pretreated patients. However, none of the patients receiving thalidomide during refractory relapse responded. Among the 10 previously treated patients, responses were observed only in patients with 2 years duration of prior treatment (Table 2). All pretreated patients had received chlorambucil with or without corticosteroids. Furthermore, four patients were resistant to prior treatment with nucleoside analogs, and one of these responded to thalidomide. Clinical and laboratory features of responding patients are listed in Table 3. Time to response was short in all responding patients, and at least 25% reduction of serum monoclonal protein was observed within 1 month. In all patients who eventually achieved a response, some evidence of monoclonal protein reduction was seen with the starting dose of 200 mg. Responding patients demonstrated an increase of hemoglobin and reduction of bone marrow lymphocytosis, lymphadenopathy, and splenomegaly. Whenever elevated, serum B2-microglobulin levels decreased after treatment (Table 3) (Fig 1). Figure 2 shows changes of hemoglobin, monoclonal protein, platelets, and bone marrow lymphocytosis before and after thalidomide treatment in patients who did not achieve an objective response. In patients who were rated as stable disease (Fig 2A), these parameters remained unchanged during the study. In most patients with progressive disease, a decrease of hemoglobin was noted while the platelet count remained stable (Fig 2B). After response was achieved, responding patients were maintained on low-dose thalidomide (200 mg PO in three patients and 100 mg PO in two patients). Patient no. 1 experienced disease recurrence while receiving thalidomide. In patient no. 2, thalidomide was discontinued 8 months after initiation of treatment because of grade 2 peripheral neuropathy; 9 months later the patient remains in response. Patient no. 4 suffered from a chronic atrial

3 3598 DIMOPOULOS ET AL Fig 1. Changes of Hemoglobin (Hb, g/l), monoclonal protein (M, g/l), platelets (Plt, /L) and bone marrow lymphocytosis (BM, %) before (pre) and after (post) treatment with thalidomide in responding patients. fibrillation and died of an embolic cerebrovascular accident 5 months after initiation of thalidomide. The remaining two responding patients receive low-dose thalidomide without impairment of daily activities (Table 3). Toxicity and Thalidomide Dose Some form of adverse side effects were observed in all patients (Table 4). They were rated as grade 1 or 2 on the World Health Organization scale, with the exception of two patients who developed grade 3 constipation and two patients who developed grade 3 somnolence. The more common adverse effects were constipation, somnolence, and fatigue. Approximately one third of patients developed mood changes, depression, and tremor. Constipation, somnolence, fatigue, and mood changes occurred more often in patients older than 70 years (Table 4). The median maxi- Fig 2. (A) Changes of hemoglobin, monoclonal protein, platelets, and bone marrow lymphocytosis before and after treatment with thalidomide in patients with stable disease; (B) changes of the same parameters in patients with progressive disease.

4 THALIDOMIDE FOR MACROGLOBULINEMIA 3599 Table 3. Clinical and Laboratory Data of Responding Patients Patient No Sex Fe Fe Fe Fe Fe Age, years Disease status UN 1R UN 1R UN Prior treatment None Chl, F None Chl None Light chain Hgb, g/l* 104/ / / / /127 M-peak, g/l* 19/8 43/3.5 39/15 22/5 26/12 IgG, mg/dl* 778/ / / / /559 IgA, mg/dl* 51/140 49/128 33/40 369/281 42/56 B2-m, mg/l* 2.8/ / / / /1.3 BM lymphs, %* 20/10 50/5 45/8 40/20 10/10 LN increase NA CR NA PR NA Spleen increase NA NA NA CR NA Thalidomide maximum dose, mg Months to response Months of response Abbreviations: Fe, female; UN, previously untreated; 1R, primary refractory; Chl, chlorambucil; F, fludarabine; Hgb, hemoglobin; LN, lymph nodes; NA, not applicable; CR, complete response; PR, partial response; B2-m, B2-macroglobulin; BM lymphs, bone marrow lymphocytes. *Prethalidomide values/postthalidamide values. mum dose of thalidomide in patients 70 years of age was 400 mg (range, 200 to 600 mg), and for patients older than 70 years, it was 400 mg (range, 200 to 600 mg). Despite the small number of patients, we noted a higher incidence of side effects, such as constipation, morning somnolence, and mood changes, when the dose of thalidomide was increased from 200 mg to 400 mg daily. Peripheral neuropathy occurred in five patients and obligated discontinuation of treatment in three patients and dose reduction in two patients. No patient developed deep vein thrombosis. One patient developed pneumonia during the first month of thalidomide. One responding patient with chronic atrial fibrillation died of an embolic cerebrovascular accident 5 months after initiation of treatment; her death was not attributed to thalidomide. The dose of thalidomide was escalated to the target dose of 600 mg in only five patients (25%); their median age was 64 years. The remaining 15 patients received 400 mg maximum dose of thalidomide including five patients who were able to tolerate a maximum dose of only 200 mg. The median age of these 15 patients was 76 years. The reason for not reaching the target dose of thalidomide was intolerance in nine patients and evidence of progressive disease in six patients. Among the five responding patients, the maximum dose of thalidomide was 400 mg PO daily in four patients and 200 mg PO daily in one patient. The dose of thalido- Table 4. Incidence of Adverse Effects % of Patients Daily Maximum Dose of Thalidomide Adverse Effect All (n 20) 70 Years (n 8) 70 Years (n 12) 20 mg (n 20) 400 mg (n 15) 600 mg (n 5) Constipation Somnolence and/or fatigue Mood changes or depression Tremor Headache Xerostomia Edema Peripheral neuropathy Skin rash Neutropenia

5 3600 DIMOPOULOS ET AL mide was not escalated further because of side effects. The median maximum dose tolerated by the 15 patients not achieving at least a partial response was 400 mg PO daily. More specifically, four patients received 200 mg, six patients received 400 mg, and five patients received 600 mg PO daily. Thus, there was no obvious difference in the maximum dose tolerated by the responding and the nonresponding patients, and none of the five patients in whom the dose of thalidomide could be escalated to the maximum dose of 600 mg achieved a response. The daily average dose of thalidomide was 300 mg (range, 100 to 600 mg). Ten patients received thalidomide for 2 months, including three patients who discontinued thalidomide within 30 days of treatment. The reason for early discontinuation of treatment was drug intolerance in seven patients and early disease progression in three patiens. If we exclude the seven patients who received thalidomide for less than 2 months because of side effects, five of the 13 remaining patients responded to thalidomide. Four patients received thalidomide for more than 2 months to 4 months, and six patients received thalidomide for more than 4 months. Among the 10 patients who received thalidomide for more than 2 months, intolerance was the reason for interruption in two patients. DISCUSSION Singhal et al 7 first demonstrated that thalidomide has significant activity in one third of patients with refractory myeloma. This activity was subsequently confirmed by other studies as well Based on these data, we conducted a prospective evaluation of thalidomide in patients with WM, a plasma cell dyscrasia that shares similarities with multiple myeloma and with low-grade lymphomas. We found that thalidomide had antitumor activity in 25% of patients with WM. These patients experienced at least 50% reduction of serum monoclonal protein, and this decline was accompanied by a reduction of tumor infiltration at all involved sites, an increase in hemoglobin levels, and decrease of elevated B2-microglobulin levels. No minor responses were noted; in five patients, the disease remained stable for a median of 4 months; and 15 patients experienced early disease progression. In patients who did not achieve a partial response, there was no improvement of baseline anemia or thrombocytopenia. As in multiple myeloma, all responding patients showed evidence of antitumor effect within 2 months; therefore, trials longer than 3 months may not be necessary to assess disease sensitivity. Our patient population was not large enough to make formal correlations between pretreatment characteristics and the probability of response. It may be of interest to note that all responding patients were female and that the activity of thalidomide did not seem different in previously untreated or pretreated patients. However, all responding patients were either untreated or primary refractory to treatment, including one patient with prior resistance to fludarabine. Furthermore, none of the seven patients with disease duration longer than 2 years responded to thalidomide. The antitumor mechanisms of thalidomide in multiple myeloma are probably complex and not clearly defined. Possible mechanisms of action include inhibition of angiogenesis, modulation of adhesion molecules involved in the interaction of myeloma cells and bone marrow stroma, modulation of several cytokines that may affect the survival of myeloma cells, and induction of secretion of interferonalfa and interleukin-2 by CD8 T cells. 16 Some recent studies in myeloma indicate that elevated blood levels of angiogenesis factors, such as basic fibroblast growth factor and vascular endothelial growth factor, are associated with a higher likelihood of response to thalidomide. 17,18 Other studies, however, could not detect an association between bone marrow microvessel density and angiogenesis grade with response to thalidomide, and this agent did not affect vascular endothelial growth factor secretion in myeloma cell lines. 19,20 A preliminary study in patients with WM patients indicated that bone marrow microvessel density was increased in a minority of patients. 21 Hideshima et al 15 reported recently that thalidomide and its analogs may have a direct antimyeloma effect by inducing apoptosis or cell cycle arrest. The mechanisms of action of thalidomide in macroglobulinemia have not been evaluated. The rapid responses usually observed in our patients were consistent with a direct cytotoxic effect on tumor cells or with an immunomodulatory effect of thalidomide. Future studies need to assess possible correlations of elevated blood concentrations of angiogenesis factors and of bone marrow angiogenesis with the likelihood of response. Almost all our patients experienced side effects from thalidomide, the most common being constipation, somnolence, and fatigue. Approximately one third of patients also developed mood changes or depression, tremor, and some evidence of peripheral neuropathy. These side effects were not life threatening and were reversible after dose reduction or interruption of therapy. However, the dose of thalidomide was escalated to the target dose of 600 mg in only five patients (25%). Furthermore, seven patients (35%) received thalidomide for 2 months because of drug intolerance. Data from myeloma series indicate that there may be an increased incidence of thalidomide s side effects in older patients. 10,22 The median age of our patient population (74 years) was 10 to 15 years higher than the median age in all previously published studies of patients with multiple myeloma, and this may explain the frequency of side effects in

6 THALIDOMIDE FOR MACROGLOBULINEMIA our study. We also noted a higher incidence of side effects such as constipation, somnolence, and mood changes when the dose of thalidomide was increased from 200 mg to 400 mg daily. In all patients who eventually achieved a response, some evidence of monoclonal protein reduction was seen with the starting dose of 200 mg. Because in all patients there was an attempt to increase the dose of thalidomide at 2-week intervals, we were not able to assess whether there was a dose-response relation. However, we noted that none of the five patients in whom the dose of thalidomide could be 3601 escalated to the maximum daily dose of 600 achieved a response. Based on these observations, we propose that future studies of thalidomide in macroglobulinemia should focus on prolonged administration of thalidomide at low daily dose, ie, 200 mg. Our data indicate that thalidomide has activity in WM. If this observation is confirmed, and because thalidomide is not associated with myelosuppression, studies that will combine thalidomide, at low doses, with chemotherapy or with rituximab may be relevant. Furthermore, thalidomide may be also studied in patients with other types of low-grade lymphoma. 1. Kyle RA, Garton JP: The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc 62: , Dimopoulos MA, Alexanian R: Waldenstrom s macroglobulinemia. Blood 83: , Dimopoulos MA, Panayiotidis P, Moulopoulos LA: Waldenstrom s macroglobulinemia: Clinical features, complications and management. J Clin Oncol 18: , Kyle RA, Greipp PR, Gertz MA, et al: Waldenstrom s macroglobulinemia: A prospective study comparing daily with intermittent oral chlorambucil. Br J Haematol 108: , Desikan R, Dhodapkar M, Siegel D, et al: High-dose therapy with autologous haemopoietic stem cell support for Waldenstrom s macroglobulinaemia. Br J Haematol 105: , Byrd JC, White CA, Link B, et al: Rituximab therapy in Waldenstrom s macroglobulinemia: Preliminary evidence of clinical activity. Ann Oncol 10: , Singhal S, Mehta J, Desikan R, et al: Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 341: , Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: , Dimopoulos MA, Kantarjian H, Weber D, et al: Primary therapy of Waldenstrom s macroglobulinemia with 2-chlorodeoxyadenosine. J Clin Oncol 12: , Juliusson G, Celsing F, Tureson I, et al: Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma. Br J Haematol 109:89-96, Yakoub-Agha I, Moreau P, Leyvraz S, et al: Thalidomide in patients with advanced multiple myeloma. Hematology J 1: , Alexanian R, Weber D: Thalidomide for resistant and relapsing myeloma. Semin Hematol 37:22-25, 2000 (suppl 1) REFERENCES 13. Rajkumar SR, Fonseca R, Dispenzieri A, et al: Thalidomide in the treatment of relapsed multiple myeloma. Mayo Clin Proc 75: , Barlogie B, Spencer T, Tricot G, et al: Long term follow up of 169 patients receiving a phase II trial of single agent thalidomide for advanced and refractory multiple myeloma. Blood 96:514a, 2000 (abstr 2213) 15. Hideshima T, Chauhan D, Shima Y, et al: Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96: , Raje N, Anderson K: Thalidomide: A revival story. N Engl J Med 341: , Neben K, Moehler T, Egerer G, et al: High plasma basic fibroblast growth factor concentration is associated with response to thalidomide in progressive multiple myeloma. Blood 96:167a, 2000 (abstr 721) 18. Weber DM, Rankin K, Gavino M, et al: Angiogenesis factors and sensitivity to thalidomide in previously untreated multiple myeloma. Blood 96:168a, 2000 (abstr 724) 19. Rajkumar SV, Fonseca R, Dispenzieri A, et al: A phase II trial of thalidomide in the treatment of relapsed multiple myeloma with laboratory correlative studies. Blood 96:168a, 2000 (abstr 723) 20. Rajkumar SV, Timm M, Mesa RA, et al: Effect of thalidomide on myeloma cell apoptosis and VEGF secretion. Blood 96:364a, 2000 (abstr 1574) 21. Haymans SR, Fonseca R, Dispenzieri A, et al: Bone marrow angiogenesis in Waldenstrom s macroglobulinemia. Blood 96:754a, 2000 (abstr 3261) 22. Alexanian R, Anderson KC, Barlogie B, et al: Thalidomide in hematologic malignancies: Future directions. Semin Hematol 37:35-39, 2000 (suppl 1)