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Fludarabine Therapy in Macroglobulinemic Lymphoma By Hagop M. Kantarjian, Raymond Alexanian, Charles A. Koller, Razelle Kurzrock, and Michael J. Keating Fludarabine, a fluorinated analogue of adenine, was given to 11 patients with macroglobulinemiclymphoma, all but one having failed prior standard chemotherapy. Five patients (45%)respondedwith more than a 50% reductionof immunoglobulin M (IgM) tumor mass for a projected median duration of longer than 1 year. The onset of remission was usually slow, with a median tumor halvingtime of 5.2 months in responding patients, emphasizing the importance of repeated courses of treatment. Fludarabineis an important new agent effective against macroglobulinemic lymphoma, and should be evaluated further in combination with other active modalities. 0 1990 by The American Society of Hematology. WALDENSTROM'S macroglobulinemia, or macroglobulinemic lymphoma, is a generalized chronic lymphoproliferative disorder characterized by the production of a monoclonal immunoglobulin M (IgM) by welldifferentiated plasmacytic lymphocytes.'-' Clinical features include hyperviscosity syndrome, anemia, splenomegaly, lymphadenopathy, and peripheral lymphocytosis. Treatment has consisted usually of plasmapheresis for hyperviscosity and combinations of alkylating agents and steroids for the (range, 930 to 8,600 g/100 mL). Seven patients had bone marrow involvement,four of them having peripheral lymphocytosis.Despite the presence of less than 30% lymphocytes in the bone marrow in patients 4,7,8, and 11,two of them (patients 7 and 8) had evidence of monoclonal lymphocytic proliferation in the bone marrow by immunophenotyping. The other two patients did not have immunophenotyping done on their marrows. One patient (patient 2) had palpable splenomegaly 25 cm below the costal margin (bcm). Two patients (patients 2 and 5) had palpable hepatomegaly 2 cm and 5 cm bcm, respectively. Three patients (patients 4, 9, and 10) had m a l i g n a n ~ y .N~ o- ~guidelines or effective therapies have been peripherallymphadenopathy.The patients'median hemoglobin was promulgated for the treatment of patients resistant to stan- 10.1 g/dL (range, 7.1 to 13.5 g/dL), and their median white blood dard regimens. cell (WBC) count was 4.8 x 103/pL(range, 1.4 to 17.9 x 103/pL). Fludarabine (9-~-d-arabinofuranosyl-2-fluoro-adenine Three had platelet counts below 100 x 103/pL(Table 1).All but one monophosphate) is a fluorinated analogue of adenine. The antitumor activity may be due to inhibition of DNA polymerase and ribonucleotide reductase by the active phosphory- had received multiple courses of prior chemotherapywith combinations of alkylating agents, steroids, anthracyclines,and interferons. The median number of prior regimens was four. Disease progression, defined as greater than 25% increase in tumor mass while on the lated product, fludarabine triphosphase, as well as by its immediateprevious therapy, was observed in 7 of 10 patients (Table incorporation into DNA, producing inhibition of D N A 1). synthesis and cell death. Fludarabine has been the most Fludarabine was given in a dose of 30 mg/m2 intravenously over active single agent for chronic lymphocytic leukemia6 and 30 minutesdaily for 5 consecutivedays.Courses were repeated every has also demonstrated antitumor efficacy in other indolent 4 weeks, provided the white blood cells had recovered to 2.5 x lymphomas.' In this article, we report on the high frequency of response induced by fludarabine in patients with macroglobulinemic lymphoma, most of them having failed prior standard therapy. 103/pLand the platelets to 100 x 103/pL, unless low values were attributed to extensive marrow infiltrationby lymphocytes. Response criteria were similar to those applied in evaluating therapeutic results in multiple myeloma.8Response was defined as a sustained decrease in the production rate of monoclonal IgM on PATIENTS AND METHODS Eleven patients with macroglobulinemic lymphoma were treated with fludarabine after informed consent was obtained according to institutionalguidelines. The diagnosis was confirmed by the presence electrophoresis by more than 50%, on at least two measurements at 2-week intervals with at least a partial response (PR) in all other involved organ sites.' Patients with mixed responses were considered failures. of (1)unequivocalinfiltrationof well-differentiatedlymphocytesand atypical or lymphocytic plasma cells in biopsies from involved RESULTS organs, and (2) a monoclonal IgM peak on immunoelectrophoresis. The patients'characteristics are shown in Table 1. Median age was 57 years (range, 43 to 67 years), and eight (73%) were males. The median time from diagnosis to the start of therapy was 40 months (range,0 to 94 months).The median IgM level was 2,500 g/lOO mL Response. Five of eleven patients (45%) responded with a greater than 50% reduction of monoclonal IgM production; three had a 75% or greater reduction. In addition, all five patients had at least a P R in other sites of disease involvement (Table 2). In patient 6, IgM levels decreased from 8,600 mg/100 mL to 4,175 mg/100 mL after three courses ~~ From the Departments of Hematology, and Clinical Immunology and Biological Therapy, University of Texas M.D. Anderson of fludarabine with normalization of blood and bone marrow lymphocytosis. He was considered unresponsive because only Cancer Center. Houston, TX. one electrophoresis was conducted during remission. Ther- Submitted October 13. 1989; accepted January 16, 1990. apy was withheld because of non-A, non-B hepatitis, and his Address reprint requests to Hagop M. Kantarjian, MD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 61, Houston, TX 77030. Thepublication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C.section 1734 solely to indicate thisfact. 0 1990 by The American Society of Hematology. 0006-4971/90/7510-0008%3.00/0 disease relapsed 2 months later. The median time of tumor halving among responders was 5.2 months (range, 1.6 to 6.8 months). Figure 1 shows changes in calculated tumor mass in two responding patients. Responses have lasted for 9, l o + , l o + , 14+, and 19+ months, respectively. Considering the small number of patients, we could not demonstrate any trends between patient characteristics, such 1928 Blood, Vol 75, No 10 (May 15). 1990: pp 1928-1931 Table 1. Patient Characteristics Patient No. Age (vrs)/Sex Duration of Disease (mos) Pretreatment Peripheral Marrow Hemoglobin Platelet Count WBC Count Lymphocyte Lymphocytes IgM (a/&) ( X 1 0 ~ 1 ~ ~( X) 103/p~) (%I (%) (d100mL) Prior Therapy Response/Duration Status/Survival Disease Status (mos) (mod Responders 1 2 3 52/F 49/F 66/M 4 5 Nonresponders 6 7 8 9 10 11 59/M 53/M 67/M 49/M 57/F 59/M 64/M 43/M 90 0 74 94 32 40 15 93 33 66 14 10.1 7.2 10.1 10.1 9.9 7.3 13.5 9.9 7.1 10.9 11.8 135 101 24 199 79 8 320 355 185 172 145 3.9 4.4 17.9 3.9 4.1 1.4 6.8 4.9 7.0 4.8 5.3 55 54 90 27 94 41 43 6 18 32 31 30 1.1 10.0 Chl,P,IFN-A 52 9,060.0 - Stable - +Response/ 19 Alive/22+ + +Response/ 14 Alive/ 17 81 7,000.0 Melphalan,P,VCAP,Chl,IFN-G, Progressive Response/S Dead12 1 splenectomy,VAD +14 1,185.0 Chl,CVP,VAD,IFN-A,MTX,V-D Progressive Response/l O+ Alive/ 13 87 1,010.0 C,MTX,V,P,IFN-A + +Progressive Response/ 10 Alive/ 13 61 8,600.0 IFN-A,Chl,P,CVP,A 20 930.0 VAD 29 4,050.0 C,Chl,P,IFN-A 60 1,700.0 Chl.lFN-G,VAD 69 2,500.0 Chl,lFN-G 27 3,800.0 BCNU,C,P,V Progressive Progessive Progressive Progressive Stable Stable Fail Fail Fail Fail Fail Fail Dead/? +Alive/5 +Alive14 +Dead13 Dead/ 12 +Alive/ 19 Abbreviations: V, vincristine; C, cyclophosphamide; A, Adriamycin; Chl, chlorambucil; P, prednisone; MTX, methotrexate; VAD, vincristine-Adriamycin-dexamethasone;IFN-A, alfa interferon; IFN-G, gamma interferon. Patient No./ No. Courses 112 Time to Therapy Pre Post IgM (g/lOO mL) 1,110 198 IgM Reduction (%I 94 219 Pre Post 318 Pre Post 9,060 2.9 10 7.000 1.2 75 87 75 415 Pre Post 1,185 310 59 516 Pre Post 1,010 370 57 Abbreviations: LN, lymph nodes; bcm, below costal margin. Hemoglobin (a/&) 10.1 11.1 7.2 12.8 10.1 10.8 10.1 12.1 9.9 13.2 Table 2. Response Patterns Platelets ( x 1o w ) 135 135 101 167 24 126 199 116 79 376 Marrow Lymphocytes (%) 30 5 52 13 81 20 14 10 87 11 Site of Involvement Peripheral Lymphocytes (%I Absolute Lymphocyte Count ( x 10 3 / ~ ) 55 2.1 25 0.5 54 2.4 11 0.3 90 16.1 10 0.9 27 1.1 16 0.7 94 3.9 21 0.5 Other Organs Spleen (cm bcm) Liver (cm bcm) 25 3 00 Axillarv LN (cm) lnauinal LN (cm) ~~ 3x3 3x3 00 Liver (cm bcm) Abdominal LN (cm) 5 56 0 52 A W N W 1930 100 90 80 70 3 60 50 L -50 40 I- f 30 c 5 !! -4- n!! 20 -0 3 r0 10 2 8 6 Patient 1 Patient 2 100 90 80 70 60 50 40 30 20 10 8 ~~ 123456 6 123456 Months of Treatment KANTARJIAN ET AL Fig 1. Reduction of calculated tumor mass in two patients with macroglobulinemic lymphoma responding to fludarabine. as age, duration of disease, extent of prior therapy, or IgM levels, and response to fludarabine (Table 1). The details of the response patterns among the five responders are shown in Table 2. After two courses of fludarabine, patient 1 obtained a 94%reduction in the IgM tumor mass, and a decrease of the peripheral lymphocytosis from 55% to 25%. She remains in remission 14 months after discontinuation of therapy. Patient 2 has achieved a nodular partial response (residual lymphoid nodules) in the bone marrow, and complete response of her massive splenomegaly. In addition, the IgM tumor mass was reduced by 87%. She continues to receive fludarabine therapy. Patient 3 achieved a complete remission in the peripheral blood and bone marrow, in addition to a 75% tumor mass reduction. Treat- ment was stopped after eight courses of fludarabine. He developed a second primary malignancy, a squamous cell carcinoma of the glottis and larynx, and died 13 months after treatment was discontinued. Patient 4 has received a total of five courses of fludarabine, achieving a complete regression of bilateral axillary lymphadenopathy from 3 x 3 cm to nonpalpable, and a partial regression of bilateral inguinal lymph nodes from 3 x 3 cm to 1 x 1 cm. IgM tumor mass was also reduced by 59%.Patient 5 is continuing on therapy. After six cycles of fludarabine, he had obtained a complete response in the peripheral blood, marrow, and liver and a P R in the extensive abdominal lymphadenopathy consisting of numerous (more than 10) enlarged lymph nodes up to 6 cm each, which have all decreased to 2 cm or less. Toxicity. The side-effects associated with treatment were usually mild and reversible. Mild thrombocytopenia (50 to 100 x 103/pL) was observed in two patients, and infections occurred in three patients. One patient developed fever with normal granulocyte counts that responded to antibiotic therapy; another patient (patient 6) developed a dental abscess and non-A, non-B hepatitis; a third developed a herpes simplex infection during the fourth course, bronchitis during the seventh course, and herpes zoster during the ninth course. DISCUSSION Few reports are available on the treatment of patients with macroglobulinemic lymphoma. Alkylating agents, such as chlorambucil and cyclosphosphamide, in combination with glucocorticosteroids, have been used most frequently as the primary treatment for the disease. Most patients respond to varying degrees and for various durations; the median survival time is about 4 years. No guidelines or effective therapies are available for patients resistant to these standard regimen^.'.^ In this report, we describe the use of a new agent, fludarabine, which has produced remissions of good quality in a high proportion of patients with macroglobulinemic lymphoma resistant to standard therapy. Response criteria were rigid and based on unequivocal and sustained reductions of both monoclonal IgM production and tumor mass. Responses were usually slow in onset and required multiple courses of treatment, but were durable in nature. Complete disappearance of IgM tumor mass was not obtained, in contrast to the results with intensive chemotherapy (M2 protocol).'Side effects were infrequent, mild in degree, and reversible. The number of patients was too small to yield any prognostic trends regarding predictive factors for response to fludarabine. However, four of the five responding patients were either untreated (one patient), or had long periods of disease control with prior chemotherapy. Because of the rarity of macroglobulinemic lymphoma, experience with chemotherapy or biologic treatment is fragmentary.'-I3 Gomez et a1 reported responses in two patients FLUDARABINE THERAPY IN MACROGLOBULINEMIC LYMPHOMA 1931 who received vincristine, bleomycin, and predni~oneP.~ihlstedt emphasized the value of plasma exchange and moderate doses of cytostatics in achieving durable responses." One patient treated with pentostatin by Riddell et a1also achieved a significant response.'' Ohno et a1 described one responder among three patients who received recombinant alpha or lymphoblastoid interferon.I2 Finally, Quesada et a1 observed no objective responses among five patients treated with recombinant gamma interfer~n.'~ In summary, this experience with fludarabine suggests a high level of antitumor efficacy in patients with advanced macroglobulinemic lymphoma, as was also seen among patients with other indolent B cell neoplasm^.^.' The activity in patients resistant to standard therapy suggested even greater use might be shown in newly diagnosed patients, or among those in partial remission with other treatments. Further studies involving combinations of fludarabine and other active agents and during remission consolidation may improve the response rate and remission time of patients with macroglobulinemic lymphoma. ACKNOWLEDGMENT We thank Kay Delasalle for her excellent technical assistance. REFERENCES 1. Waldenstrom J: Incipient myelomatosis or "essential" hyperglobulinemia with fibrinogenopenia-a new syndrome? Acta Med Scand 117:216,1944 2. McCallister BD, Bayrd ED, Harrison EG, McGuckin W: Primary macroglobulinemia-review with a report on 31 cases and notes on the value of continuous chlorambucil therapy. Am J Med 43:394, 1967 3. MacKenzie MR, Fudenberg HH: Macroglobulinemia-an analysis of forty patients. Blood 39:874, 1972 4. Fahey JL, Barth WF, Solomon A: Serum hyperviscosity syndrome. JAMA 192:464, 1965 5. Case DC Jr: Combination chemotherapy (M-2) protocol (BCNU, cyclophosphamide,vincristine, melphalan, and prednisone) for Waldenstrom's macroglobulinemia. Blood 59:934, 1982 6. Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie KB: Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74:19, 1989 7. Redman J, Cabanillas F, McLaughlin P, Hagemeister F, Velasquez W, Swan F, Rodriguez M, Plunkett W, Keating M: Fludarabine phosphate-a new agent with major activity in low grade lymphoma. Proc AACR 29:211, 1988 (abstr 840) 8. McLaughlin P, Alexanian R:Myeloma protein kinetics follow- ing chemotherapy. Blood 60:851,1982 9. Gomez GA, Han T, Ozer H, Henderson ES: Treatment of refractory lymphoproliferative diseases with daily, low-dosevincristine, continuous infusion of bleomycin, and high-dose prednisone. Med Pediatr Oncol 12:239, 1984 10. Pihlstedt P Plasma exchange and moderate dose of cytostat- ics in advanced macro(cryo)globulinemia. Acta Med Scand 212: 187,1982 11. Riddell S, Johnston J, Rayner H, Israel L: Response of Waldenstrom'smacroglobulinemiato pentostatin (2'Deoxycoformycin). Cancer Treat Rep 70546, 1986 12. Ohno R, Kodera Y, Ogura M, et al: Treatment of plasma cell neoplasma with recombinant leukocyte A interferon and human lymphoblastoid interferon. Cancer Chemother Pharmacol 14:34, 1985 13. Quesada JR, Alexanian R, Kurzrock R, Barlogie B, Saks S, Gutterman JU: Recombinant interferon gamma in hairy cell leukemia, multiple myeloma, and Waldenstrom's macroglobulinemia. Am J Hematol29:1, 1988