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Primary Therapy of Waldenstriim's Macroglobulinemia With 2-Chlorodeoxyadenosine By Meletios A. Dimopoulos, Hagop Kantarjian, Donna Weber, Susan O'Brien, Elihu Estey, Kay Delasalle, Esther Rose, Fernando Cabanillas, Michael Keating, and Raymond Alexanian Purpose: To assess the activity of 2-chlorodeoxyadenosine (2CdA) as primarytherapy for patients with Waldenstrim's macroglobulinemia. Patients andMethods: 2CdA was given to 26 consecutive, previously untreated and symptomatic patients with Waldenstr6m's macroglobulinemia. Two courses were administered to outpatients at a dose of 0.1 mg/ kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed up without further therapy and were scheduled to receive two additional treatments with 2CdA on disease relapse. Results: Twenty-two of 26 patients responded to the 2C-ildrapy (85%; 95%confidence interval [CI], 65%to 96%), including three patients who achieved a complete W ALDENSTROM'S macroglobulinemia is a smallcell lymphocytic lymphoma that produces monoclonal immunoglobulin M (IgM). The disease usually affects older persons and may cause symptoms due to anemia, lymphadenopathy, or elevated serum viscosity.1 Chemotherapy with alkylating agents and steroids has been the standard therapy for patients with symptomatic macroglobulinemia and has induced responses in about one half of previously untreated patients. Courses have been usually administered intermittently for long periods and have exposed patients to the risks of myelosuppression and rarely secondary leukemia.2-6 We have recently reported that the nucleoside analog 2chlorodeoxyadenosine (2CdA) was active in 40% of patients with macroglobulinemia who had failed previous therapies.7 A few previously untreated patients were included in this study, and their disease appeared to be sensitive to this agent. Based on this encouraging experience, we studied 2CdA as the initial therapy for a larger number of patients with Waldenstriim's macroglobulinemia. PATIENTS AND METHODS Between January 1991 and March 1994, 26 previously untreated patients with Waldenstrim's macroglobulinemia were treated with From the Department of Hematology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Submitted March 15, 1994; accepted July 1, 1994. Supported by the Robert Hompe Myeloma Research Fund. Address reprint requests to Meletios A. Dimopoulos, MD, 227 Kifissias Ave, 14561 Kifissia, Athens, Greece. 1994 by American Society of Clinical Oncology. 0732-183X/94/1212-0000$3.00/0 response and 19 patients who had a partial response. Treatmentwas well tolerated, with no acute hematologic toxicity. A marked and sustained reduction of CD4+ lymphocytes occurred in all patients and may have contributed to a fatal infection with disseminated herpes simplex in one patient. With a median follow-up of 13 months, five patients have relapsed and all re-treated patients have responded again to 2CdA. Conclusion: 2CdA is highly active in previously untreated patients with Waldenstr6m's macroglobulinemia. A limited program of treatment induced responses of good quality and long duration in more than 80% of patients. J Clin Oncol 12:2694-2698. 1994 by American Society of Clinical Oncology. 2CdA (R.W. Johnson Pharmaceutical Company, Ortho Biotech Inc, Raritan, NJ) after informed consent was obtained according to institutional guidelines. Patients' characteristics are shown in Table 1. The median age was 65 years (range, 35 to 88 years), and 16 were male. The primary reasons for treatment were worsening anemia (nine patients); lymphadenopathy or organomegaly (eight patients); hyperviscosity syndrome (five patients); weight loss, night sweats, or fever (two patients); cryoglobulinemia (one patient); and peripheral neuropathy (one patient). Two patients were referred to us with advanced Waldenstrim's macroglobulinemia and concurrent metastatic adenocarcinoma of unknown primary origin (diagnosed 3 months earlier) and metastatic squamous cell carcinoma of the skin (diagnosed 10 months earlier). Because none of the patients had previously received chemotherapy and because both had severe anemia and hyperviscosity syndrome, they were treated with 2CdA. All patients had baseline evaluations that included blood counts, hepatic and renal function tests, bone marrow aspirate, immunophenotype and biopsy, quantitation of CD4+ and CD8+ blood lymphocytes, serum and urine protein electrophoreses, quantitation of serum Igs and /32-microglobulin. Chest x-ray and computed tomography of the abdomen and pelvis were also performed. While on treatment, patients were followed up with weekly blood cell counts; serum electrophoretic studies were repeated monthly and complete restaging was done after completion of therapy. 2CdA was administered to outpatients at a dose of 0.1 mg/kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Two courses of 2CdA were given 4 weeks apart and responding patients were followed without further therapy until disease relapse when treatment with two courses of CdA was resumed. Patients who did not respond to primary therapy with 2CdA were treated with a combination of chlorambucil and prednisone. Response criteria were adapted from those used at our center in evaluating patients with multiple myeloma and from previously published studies of Waldenstrim's macroglobulinemia.2" Partial response was defined as a sustained decrease by at least 50% of monoclonal IgM concentration for at least 2 months; responding patients were also required to achieve more than 50% reduction of 2694 Journalof Clinical Oncology, Vol 12, No 12 (December), 1994: pp 2694-2698 Downloaded from jco.ascopubs.org on September 7, 2010. For personal use only. No other uses without permission. Copyright 1994 American Society of Clinical Oncology. All rights reserved. 2-CHLORODEOXYADENOSINE FOR MACROGLOBULINEMIA 2695 Table 1. Patient Characteristics Patients No. % Response* No. % Total 26 22 85 Age > 60 years 15 58 12 80 Lymphadenopathy 12 46 11 92 Splenomegaly 6 23 4 67 Hemoglobin < 100 g/L 14 54 14 100 #2-microglobulin > 4.0 mg/L 8 32 8 100 Serum peak > 20 g/L 15 58 13 87 Bone marrow lymphocytes > 25% 12 46 11 92 *Response defined by reduction of serum monoclonal IgM level to < 50% of pretreatment level. tumor infiltrate at all involved sites. Complete response was defined as disappearance of the monoclonal protein by immunofixation, resolution of lymphadenopathy and splenomegaly, and less than 20% lymphocytes in the bone marrow. Relapse was defined by at least a 25% increase of monoclonal protein from the lowest value or reappearance of lymphadenopathy or anemia. Progression-free survival, overall survival, and diseasespecific survival were calculated using the method of Kaplan and Meier.' In the calculation of progression-free survival, patients who died in remission from an unrelated cause were censored at the time of death. RESULTS Response Of 26 patients, 19 achieved a partial response and three a complete response for an overall response rate of 85% (95% confidence interval [CI], 65% to 96%). The median time to a 50% reduction of IgM synthesis was 1.2 months (range, 0.2 to 2.5 months). Even after 2CdA therapy was stopped, gradual reduction of abnormal protein continued in all responding patients along with disease reduction at all involved sites (Table 2, Fig 1). Thus, lymphadenopathy was reduced by more than 50% in all 11 responding patients and resolved in eight patients. Bone marrow lymphocytosis was reduced by at least 50% in all 11 responding patients with more than 25% infiltration. Hemoglobin values of less than 100 g/L increased by at least 20 g/L in 12 of 14 responding patients (Table 2). Serum 32-microglobulin values of greater than 4 mg/L were also reduced in all responding patients. Throbmocytopenia resolved in 2 patients with this abnormality. Four patients did not respond to 2CdA therapy. One died of cardiorespiratory arrest before further therapy was given and 3 patients remained resistant to a chlorambucil-prednisone combination. Progression-FreeSurvival With a median follow up of 13 months (range, 2+ to 39+ months), five patients (19%) have relapsed after 8 to 18 months (Fig 2). One relapsing patient has not yet received further treatment; the remaining four patients responded again to retreatment with 2CdA. One of these patients died of disseminated herpes simplex infection after 16 months of a second remission and the other three remain in a second unmaintained remission for 6+, 8+, and 12+ months. Toxicity Treatment was well tolerated and myelosuppression was mild and reversible; the median lowest neutrophil count was 1.2 x 109 /L (range, 0.3 to 5.0 X 109/L) and the median lowest platelet count was 150 X 109 /L (range, 38 to 350 109/L). The second course of treatment was administered 4 weeks after the first course without delay in all patients. One patient developed neutropenic fever, two patients developed nonneutropenic bronchitis, and one patient developed dermatomal herpes zoster. One patient developed fatal disseminated herpes simplex 16 months after retreatment with 2CdA, which was given because of recurrent disease. A marked decrease in the number of lymphocytes ex- Table 2. Clinical Response Pattern of 22 Patients Patient No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 % of Pre Rx IgM Peak 0 0 5 10 28 29 33 34 46 48 49 0 22 25 32 33 35 37 38 40 41 46 Reduction of LN Spleen CR CR PR PR CR CR CR CR PR PR CR PR CR CR CR % BM Lymphocytes Before RX After RX 45 10 22 18 20 7 13 15 93 27 30 14 16 10 94 45 66 15 33 14 47 12 36 18 20 20 85 8 35 12 22 17 11 10 40 11 20 14 24 14 82 40 11 10 Hemoglobin (g/L) Before RX After RX 78 148 130 124 91 123 96 135 68 115 120 139 113 120 97 157 84 143 119 128 94 130 120 142 93 110 72 134 97 124 114 137 130 124 95 125 96 130 98 116 85 111 102 118 Abbreviations: Rx, treatment; IgM peak, serum monoclonal IgM component; LN, lymph nodes; BM, bone marrow; CR, complete response; PR, partial response; -, not applicable. Downloaded from jco.ascopubs.org on September 7, 2010. For personal use only. No other uses without permission. Copyright 1994 American Society of Clinical Oncology. All rights reserved. 2696 -- 5.0- 4.0- a 3.0 E 2.01.0 4 \1 1 I I 024 I 8 Months of Treatment I 12 Fig 1. Sustained reduction of serum monoclonal component of IgM concentration after two courses of 2CdA. (Circles represent the median and solid lines the range of values.) pressing CD4 surface antigen (helper phenotype) occurred in all patients with a less pronounced decrease in lymphocytes expressing CD8 surface antigen (suppressor phenotype) (Table 3). To evaluate the recovery of CD4+ lymphocytopenia with time, CD4 counts were remeasured 12 months after initiation of treatment in 9 patients who responded to 2CdA and remained in remission for at least DIMOPOULOS ET AL Table 3. Lymphocyte Subsets in Patients With Waldenstrim's Macroglobulinemia Treated With 2CdA Baseline Nadir P CD4+ lymphocyte counts x 103/L* Median Range No. - 200 No. s 50 CD8+ lymphocyte counts x 10 3/Lt Median Range 764 135-5,368 2 0 509 94-2,505 112 15-390 13 3 < .01 < .01 201 50-2,100 .04 *Normal range, 365 to 2,400 x 103/L. t Normal range, 270 to 1,600 x 103/L. 12 months. The median lowest value and that at 12 months were 103 X 103/L and 150 x 103/L, respectively, indicating sustained depression for as long as 1 year. Survival With a median follow-up of 13 months, five patients (19%) have died. One patient died of disseminated herpes simplex and was rated as a treatment-related death. Four patients died of unrelated diseases that were present before the initiation of 2CdA therapy: the deaths of three responding patients were due to cerebral hemorrhage in a patient with severe hypertension, metastatic adenocarcinoma of unknown origin and metastatic squamous cell AB tae 00 3C >c=0( C0)0. C', OR 5.. C/, a, a, 0oaa) o. 0) Fig 2. (A) Overall survival (solid line) and disease-specific survival (dotted line). (B) Progression-free survival of 22 patients with macroglobulinemia responding to 2CdA. 10 20 30 40 10 20 30 40 Months of Treatment Downloaded from jco.ascopubs.org on September 7, 2010. For personal use only. No other uses without permission. Copyright 1994 American Society of Clinical Oncology. All rights reserved. 2-CHLORODEOXYADENOSINE FOR MACROGLOBULINEMIA 2697 carcinoma of the skin. Despite control of the macroglobulinemia, the growth of both solid tumors was not affected and caused the deaths 2 and 8 months later. One resistant patient with severe chronic obstructive lung disease died of cardiorespiratory arrest. Fig 2 shows the overall and disease-specific survival. DISCUSSION The standard therapy of Waldenstriim's macroglobulinemia has been alkylating agents with or without glucocorticoids. These treatments induce a response in about one half of previously untreated patients and produce a median survival of about 5 years.25 Although benefit has been reported in resistant patients who received high dose steroids, alpha or gamma interferon and fludarabine, these agents have not been studied adequately in previously untreated patients.9-12 2CdA is an adenosine deaminase-resistant purine analogue that is phosphorylated by deoxycytidine kinase and accumulates as chlorodeoxyadenosine triphosphate (chlorodATP) in cells rich in deoxycytidine kinase. ChlorodATP inhibits enzymes important in DNA repair, leading to DNA strand breaks that may accelerate the process of programmed cell death (apoptosis). 13 The observation that 2CdA exerts its cytotoxic effects independent of the cell cycle may explain its activity in patients with low-grade lymphoid neoplasms such as chronic lymphocytic leukemia, hairy-cell leukemia and low-grade B- or T-cell lymphomas.14-18 We have previously described the activity of 2CdA in patients with Waldenstr6m's macroglobulinemia, most of whom were resistant to alkylating agent-based combinations.7 In this study, a high frequency of response was observed in patients with previously untreated macroglobulinemia with only two courses of 2CdA. Eighty-five percent of patients responded and this frequency appeared higher than the 57% response rate obtained previously among similar patients treated with chlorambucil-prednisone.19 However, since patient selection and supportive care could have played a role, a randomized trial would be necessary to identify any convincing differences between these treatments. Responses to 2CdA were usually rapid in onset and continued even after the completion of treatment. The reduction of monoclonal protein was associated with resolution of symptoms, of anemia, a significant decrease of organomegaly and lymphadenopathy, and clearing of bone marrow lymphocytosis. The resolution of clinical abnormalities occurred even when the reduction of serum IgM peak barely exceeded 50%, suggesting that a complete remission of low-grade lymphoma may be associated with a substantial residual tumor load. Despite limited treatment with only two courses of 2CdA, remissions appeared durable, in most patients. Furthermore, patients with disease relapsing off therapy remained sensitive to retreatment with 2CdA, indicating that several months of disease control may be achieved with limited treatment and without the use of alkylating agents. A single course of 2CdA has induced durable responses in most patients with hairy-cell leukemia." Multiple courses of 2CdA have been given recently to previously untreated patients with chronic lymphocytic leukemia. 20 Although a high response rate was observed, there was a high incidence of severe hematologic toxicity and 17% of patients developed severe opportunistic infections. 20 In our study, despite limiting the initial treatment to two courses, CD4 lymphocytopenia was marked and sustained even in patients followed without treatment for many months and one patient who received a total of four courses of 2CdA developed fatal disseminated herpetic infection. Because opportunistic infections may occur more frequently in patients who receive 2CdA, physicians should anticipate such complications to plan an early and effective treatment.2 0'21 The impact of 2CdA therapy on survival will require longer follow-up and eventually a controlled study. Four of our patients (15%) died of conditions that appeared to be unrelated to the underlying macroglobulinemia or its therapy. Two patients died of preexisting metastatic carcinomas while their macroglobulinemia was responding to 2CdA. Although 2CdA did not appear to affect the rate of progression of the unrelated tumors, this question could not be definitively clarified by the study of only two patients. A similar frequency of unrelated deaths has been reported previously for patients with macroglobulinemia treated with alkylating agent-based therapy and for patients with chronic lymphocytic leukemia and hairy-cell leukemia. 19.22 This indicates the need to report both overall and diseasespecific survival when evaluating studies of low-grade lymphoid neoplasms in older patients. Although second primary tumors appear to develop at a higher than predicted frequency among patients with low-grade lymphoproliferative disorders, the possible effects of 2CdA on this incidence requires further study.2,5' 23,24 In summary, 2CdA is a promising agent in the primary treatment of patients with Waldenstr(im' s macroglobulinemia, inducing a high frequency of remission with minimal acute toxicity after only two courses of treatment. Longer follow-up is required to assess the clinical sig- Downloaded from jco.ascopubs.org on September 7, 2010. For personal use only. No other uses without permission. Copyright 1994 American Society of Clinical Oncology. All rights reserved. 2698 DIMOPOULOS ET AL nificance and the reversibility of cell-mediated immunosuppression as well as the impact of 2CdA on the survival of patients with Waldenstr6m's macroglobulinemia. ACKNOWLEDGMENT We are grateful to Dean Anthony and Rose Guevara for their excellent secretarial assistance. REFERENCES 1. Waldenstrom J: Incipient myelomatosis or "essential" hyperglobulinemia with fibrinogenopenia-A new syndrome? Acta Med Scand 117:216-222, 1944 2. Mackenzie MR, Fudenberg HH: Macroglobulinemia: An analysis of forty patients. Blood 39:874-889, 1972 3. Kyle RA, Garton JP: The spectrum of IgM monoclonal gammopathy in 430 cases. Mayo Clin Proc 62:719-731, 1987 4. Petrucci MT, Avvisati G, Tribalto, et al: Waldenstrom's macroglobulinemia: Results of a combined oral treatment in 34 newly diagnosed patients. J Intern Med 226:443-447, 1989 5. Case DC, Ervin TJ, Boyd MA: Long term results and disease characteristics of patients with Waldenstrom's macroglobulinemia treated with the M-2 protocol. Blood 82:561, 1993 (suppl 1) 6. Horsman DE, Card RT, Skinnider LF: Waldenstrom's macroglobulinemia terminating in acute leukemia. Am J Hematol 15:97101, 1983 7. Dimopoulos MA, Kantarjian HM, Estey EH, et al: Treatment of Waldenstrom's macroglobulinemia with 2-chlorodeoxyadenosine. Ann Intern Med 118:195-198, 1993 8. Gehan E: A generalized Wilcoxon test for comparing arbitrarily singly-censored samples. Biometrika 52:452-465, 1965 9. Jane SM, Salem HH: Treatment of resistant Waldenstrom's macroglobulinemia with high dose glucocorticoids. Aust NZ Med 18:77-78, 1988 10. Ohno R, Kodera Y, Ogura M, et al: Treatment of plasma cell neoplasm with recombinant leukocyte a-interferon and human lymphoblastoid interferon. Cancer Chemother Pharmacol 14:34-37, 1985 11. Quesada JR, Alexanian R, Kurzrock R, et al: Recombinant interferon gamma in hairy cell leukemia, multiple myeloma, and Waldenstrom's macroglobulinemia. Am J Hematol 29:1-4, 1988 12. Kantarjian HM, Alexanian R, Koller CA, et al: Fludarabine therapy in macroglobulinemic lymphoma. Blood 75:1928-1931, 1990 13. Carrera CJ, Terai C, Piro L, et al: 2-CdA chemotherapy trig- gers programmed cell death in normal and malignant lymphocytes. J Purine Pyrimidine Res 2:38-46, 1991 (suppl 1) 14. Seto S, Carrera CJ, Kubota M, et al: Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 75:377-382, 1985 15. Piro LD, Carrera CJ, Beutler E, et al: 2-chlorodeoxyadenosine: An effective new agent for the treatment of chronic lymphocytic leukemia. Blood 72:1069-1074, 1988 16. Piro LD, Carrera CJ, Carson DA, et al: Lasting remissions in hairy cell leukemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 322:1117-1121, 1990 17. Kay AC, Saven A, Carrera CJ, et al: 2-chlorodeoxyadenosine treatment of low-grade lymphomas. J Clin Oncol 10:371-377, 1992 18. Saven A, Carrera CJ, Carson DA, et al: 2-chlorodeoxyadenosine: An active agent in the treatment of cutaneous T-cell lymphoma. Blood 80:587-592, 1992 19. Dimopoulos MA, Alexanian R: Waldenstrom's macroglobulinemia. Blood 83:1452-1459, 1994 20. Saven A, Lemon RH, Kosty M, et al: 2-chlorodeoxyadenosine activity in patients with previously untreated chronic lymphocytic leukemia. Blood 82:445, 1993 (suppl 1) 21. Betticher DC, Fey MF, von Rohr A, et al: High incidence of infections after 2-chlorodeoxyadenosine therapy in patients with malignant lymphomas and chronic and acute leukemias. Ann Oncol 5:57-64, 1994 22. Facon T, Brouillard M, Duhamel A, et al: Prognostic factors in Waldenstrom's macroglobulinemia. J Clin Oncol 11:1553-1158, 1993 23. Travis LB, Curtis RE, Hankey BF, et al: Second cancers in patients with chronic lymphocytic leukemia. J Natl Cancer Inst 84:1422-1427, 1992 24. Kampmeier P, Spielberger R, Dickstein J, et al: Increased incidence of second neoplasms in patients treated with interferon a2b for hairy cell leukemia. Blood 83:2931-2938, 1994 Downloaded from jco.ascopubs.org on September 7, 2010. For personal use only. No other uses without permission. Copyright 1994 American Society of Clinical Oncology. All rights reserved.