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© 1999 American Society for Clinical Oncology Multicenter Phase II Study of Fludarabine Phosphate for Patients With Newly Diagnosed Lymphoplasmacytoid Lymphoma, Waldenström's Macroglobulinemia, and Mantle-Cell LymphomaFrom the ICRF Medical Oncology Unit and Department of Histopathology, St. Bartholomew's Hospital, London, Department of Hematology, Taunton and Somerset Hospital, Taunton, CRC Department of Medical Oncology, Christie Hospital, Manchester, and Schering Health Care Limited, Burgess Hill, West Sussex, England; Department of Hematology, Centre Hospitalier Lyon Sud, Lyon, France; Divisione di Ematologia, Ospedali Riuniti, Bergamo, Italy; and Department of Hematology, Georg-August Universität, Göttingen, Germany. Address reprint requests to J.M. Foran, MD, ICRF Medical Oncology Unit, Department of Medical Oncology, St. Bartholomew's Hospital, 45 Little Britain, 2nd Floor, London EC1A 7BE, England.
PURPOSE: Fludarabine phosphate (F-AMP) has significant activity in follicular lymphoma and in B-cell chronic lymphatic leukemia, where it has demonstrated high complete response (CR) rates. Lymphoplasmacytoid (LPC) lymphoma, Waldenström's macroglobulinemia (WM), and mantle-cell lymphoma (MCL) also present with advanced-stage disease and are incurable with standard alkylator-based chemotherapy. A phase II trial was undertaken to determine the activity of F-AMP in patients newly diagnosed with these diseases. PATIENTS AND METHODS: Between 1992 and 1996, 78 patients (aged 18 to 75 years) received intravenous F-AMP (25 mg/m2/d for 5 days, every 4 weeks) until maximum response, plus two further cycles as consolidation. The primary end point was response rate; secondary end points included time to progression (TTP), duration of response, and overall survival (OS). RESULTS: Forty-four (62%) of 71 assessable patients had a response to F-AMP (LPC lymphoma, 63%; WM, 79%; MCL, 41%); the CR rate was 15%. At a median follow-up of 1.5 years, 19 of 44 responding patients have had progression of lymphoma; the median duration of response was 2.5 years. The median survival has not yet been reached. There was no significant difference in the duration of response or OS between patients with different histologies; TTP was shorter in patients with MCL (P = .015). Myelosuppression was relatively common, and the treatment-related mortality (TRM) was 5%, mostly associated with pancytopenia and infection. CONCLUSION: Single-agent fludarabine phosphate is active in previously untreated LPC lymphoma and WM, with only moderate activity in MCL. However, the CR rate is low, and the TRM is relatively high. Its role in combination chemotherapy remains to be demonstrated.
ALKYLATING AGENTS have been the cornerstone of therapy for disseminated non-Hodgkin's lymphoma (NHL) since chlorambucil was introduced into clinical practice in 1955.1 Although not curative when given alone, they induce regression of lymphadenopathy in the majority of the previously called "low-grade" lymphomas with little toxicity2-6: achievement of clinical remission confers a survival advantage.7 Combined with other drugs, notably vinca alkaloids, corticosteroids, and more recently anthracycline antibiotics, and given cyclically, they contribute to the ability to cure a fraction of patients with aggressive lymphoma.8,9 The benefit of such combinations has not been so obvious for the less aggressive lymphomas.10,11 Hence, the introduction of another group of compounds, the purine analogs, provided a welcome opportunity for exploring new avenues of treatment in these patients. Fludarabine phosphate (F-AMP) is a fluorinated analog of adenine arabinoside that is relatively resistant to adenosine deaminase.12 It was first tested in acute leukemia and found to be excessively toxic to the nervous system at high doses.13 Several years later, it was reintroduced for chronic lymphatic leukemia at much lower doses: the results were dramatic, with compete remissions being achieved.14 Phase II trials in patients with recurrent and refractory follicular lymphoma were also promising15-18: in newly diagnosed cases, the complete response (CR) rate was 37%.19 Less attention has been paid to lymphoplasmacytoid (LPC) lymphoma, its counterpart Waldenström's macroglobulinemia (WM), and mantle-cell lymphoma (MCL).5,20-23 They are relatively uncommon diseases, accounting between them for 10% to 26% of NHLs in Western Europe.2,3,21 As a group, they commonly present in older patients, and with advanced-stage disease. They are manifestly incurable, with a low CR rate to initial therapy and a median survival period of 3 to 7 years (lowest in patients with MCL).2-6,21,24 Accordingly, a phase II trial was undertaken in patients newly diagnosed with LPC lymphoma, WM, and MCL to determine whether F-AMP could induce complete remission with a frequency high enough to justify its incorporation into the routine treatment of these diseases. The results form the basis of this report.
A phase II study of F-AMP was conducted at seven centers from June 1992 until December 1996. The primary end point of the study was to determine the complete and overall response rates (RR) in patients newly diagnosed with LPC lymphoma, WM, and MCL. Secondary end points were duration of response, time to disease progression, and survival. The study was approved by the hospital ethics committee at each of the participating institutions. Informed, written consent was obtained from each patient.
Patients
Histology was reviewed and diagnosis was assigned centrally by A.J.N. using standard Kiel criteria.20 Lymphoplasmacytoid lymphoma and WM are both "immunocytomas" in the Kiel classification. WM is a subset of the former and represents a clinicopathologic syndrome characterized by immunoglobulin (Ig) M paraproteinemia. Histologically, 40 of the 54 patients with immunocytoma on central review had lymphoplasmacytoid lymphoma, 13 had lymphoplasmacytic immunocytoma, and one had a polymorphous immunocytoma (Kiel). Patients with WM were predominantly in the lymphoplasmacytic category. For the purposes of this analysis, all patients with immunocytoma and an IgM paraproteinemia were considered to have WM (n = 20). The remaining 34 patients were considered to have LPC lymphoma. Of note, four patients in the latter category (among 31 in whom it was checked) had a paraprotein (IgG, n = 2; IgA, n = 1; class not known, n = 1). Histologic sections from three other patients were not reviewed centrally but have been included in the histologic group assigned at the individual center (LPC lymphoma, n = 2; WM, n = 1).
Treatment A baseline computed tomographic scan of the chest, abdomen, and pelvis, bone marrow aspiration, and trephine biopsy were performed, together with quantification of baseline IgM paraprotein for patients with WM. Patients were evaluated for toxicity before each cycle of therapy and for evidence of response by physical examination. Restaging studies for response were performed after every two cycles of therapy, at the end of therapy, and at the time of withdrawal from the study for any reason. Doses were modified for subsequent cycles in patients with a delay beyond 5 weeks in the recovery of the granulocyte count to more than 1.0 x 109/L and/or the platelet count to more than 100 x 109/L, unless caused by bone marrow infiltration (initial reduction to 20 mg/m2, and then to 15 mg/m2 in the event of further delays). Patients were withdrawn from the study after a further delay in blood count recovery (generally beyond 6 weeks). The last patient finished therapy in January 1997.
Twenty-six of the 78 patients had protocol deviations while receiving therapy. Eleven patients received concomitant corticosteroid therapy at some point (defined as a
Definitions Standard response criteria were applied; a response was confirmed on two consecutive visits. A complete response was defined as the disappearance of all signs of disease on the physical examination, radiologic examination, and bone marrow trephine biopsy, a normal peripheral-blood count, and the disappearance of a measurable M band for patients with WM. A partial response (PR) was indicated by regression of all measurable and assessable lymphoma by more than 50% by volume, without the appearance of new manifestations of disease, as well as a reduction of more than 50% in the M band for patients with WM. Stable disease was defined as regression of less than 50% in assessable sites of disease or progression of existing lesions by less than 25% volume. Progressive disease was defined as an increase in the volume of existing disease by more than 25% or the appearance of any new manifestations of lymphoma. Time to disease progression was determined from the date of registration until documented progression, and duration of response was determined from the date of response (CR or PR) until progression. Patients were censored in the latter two analyses at the time of the last progression-free follow-up visit if they had received any other therapy for lymphoma if progression had not been documented, or if they died while in remission. Survival was calculated from the date of registration until death or last follow-up.
Statistical Considerations
Response to Treatment Seventy-eight patients (ie, the study population) received treatment with fludarabine phosphate; seven patients (four MCL patients, two LPC lymphoma patients, and one WM patient) were not assessable for response for the following reasons: five patients were withdrawn from the study because of toxicity; one patient received concomitant radiotherapy with the first course of therapy; and no outcome assessment was performed for one patient. A complete response was achieved in 11 patients, and a PR in 33 patients. Ten patients developed progressive disease while on treatment, including one patient who developed and ultimately succumbed to histologic transformation to high-grade lymphoma. The remaining 17 patients had stable disease. The overall RR among assessable patients was therefore 62% (44 of 71). The response to treatment as determined by histology is shown in Table 2.
A total of 403 cycles of fludarabine were given to 78 patients; the mean number of treatment cycles with fludarabine was 5.2. The median time to maximum response was 2.2 months.
Time to Disease Progression and Response Duration
Survival
Toxicity
Thrombocytopenia and neutropenia were relatively common, occurring in 67 and 57 patients, respectively; they were of grade III or IV severity in six patients. At some point during treatment, nine patients required dose reductions (doses were reduced to 20 mg/m2/d in six patients and to 15 mg/m2/d in three patients). Ultimately, five patients were withdrawn from the protocol because of myelosuppressive toxicity. Neurologic side effects were relatively uncommon and relatively mild. Fourteen patients reported symptoms of asthenia and lethargy during treatment, and seven others developed insomnia, depression, or anxiety. Seven patients died in relation to treatment and are listed in Table 4. Patient no. 6 died of a major fungal infection and respiratory failure after the first cycle of treatment that was designated "unlikely" to be related to fludarabine by the individual investigator. Patient no. 7 had no response to fludarabine and developed coma from hepatorenal failure and, ultimately, sepsis more than 1 month after being withdrawn from the study. In four of seven cases, the investigating center reasoned that death was possibly, probably, or definitely related to treatment with fludarabine; therefore, the treatment-related mortality was four (~ 5%) of 84.
This study is the first to demonstrate that fludarabine phosphate, given intravenously in 5-day cycles approximately monthly, induces remission in more than half of patients with newly diagnosed lymphoplasmacytoid lymphoma and WM and in some patients with MCL. However, the complete response rate was low. It may thus be concluded that F-AMP alone has an efficacy similar to that of chlorambucil. Although it is disappointing that a higher CR rate was not achieved, the results remain encouraging. At the very least, a new drug has been introduced into the armamentarium of therapy for these incurable diseases, and it may provide useful palliation, particularly when an oral formulation is available. On a more positive note, it must be appreciated that the immediate toxicity is very low, with little significant alopecia, nausea, and vomiting. Furthermore, the mode of action of the drug is substantially different from that of alkylating agents. The response to F-AMP in patients with newly diagnosed LPC lymphoma in this trial is comparable to that seen with standard alkylator-based therapy.2-4,21 Among such patients treated at St. Bartholomew's Hospital (SBH) in the past, the overall RR was 70%; the CR rate was similarly low (12%).4 Although 15 patients (79%) with WM had a response to fludarabine phosphate, only one (5%) achieved complete remission. Treatment of WM with alkylating agents, either alone, with glucocorticoids, or in combination with doxorubicin, has shown overall response rates of 44% to 65%, although few complete responses.5 Thus, F-AMP apparently has an efficacy similar to that of existing treatments, at least in its ability to induce complete remission. Treatment with the purine analog 2-chlorodeoxyadenosine has also shown high overall response rates (85%), although again the CR rate was only 13%.26 It must be noted that the RR seen in this trial is considerably higher than that reported for the Southwest Oncology Group study (33%)27; the reasons for this are unclear but may be related to differences in response criteria and/or to patient selection. The historic response rate of patients with newly diagnosed MCL treated at SBH, using an alkylating agent alone or in combination (ie, chlorambucil ± prednisolone), was 71%, with few complete remissions (10%).3 A higher rate of complete remission, but no improvement in survival, has been reported for more intensive anthracycline-based combinations.28,29 Allowing for patient selection, single-agent F-AMP seems to have only moderate activity in comparison, with a relatively short duration of response. It cannot, therefore, be recommended for use as first-line therapy to treat MCL. Fludarabine phosphate has significant activity in patients with newly diagnosed follicular lymphoma (FL), with an overall response rate of 65%; in contrast to the present trial, however, 37% of patients had a CR.19 The lower CR rate in the present study probably relates more to the fundamental biology of the lymphoma than to patient selection, as both trials included patients with advanced-stage disease and a good performance status. The median duration of response of 2.5 years seen in this report compares favorably with the experience in FL (< 16 months). Despite this, there is no evidence of a plateau in the relapse-free survival rate in either report. Single-agent fludarabine phosphate does not, therefore, represent a cure. Fludarabine phosphate alone has also been used as treatment of recurrent and refractory low-grade NHL, with response rates in most series of 31% to 52%; however, most responses are partial.15,16,18,30,31 At SBH, the RR in that setting was 44%.17 The follow-up is too short to determine whether treatment with F-AMP has had an impact on the overall survival of patients with LPC lymphoma and WM. In this trial, the median survival for patients with LPC lymphoma has not yet been reached, consistent with other reports2-4,21: at SBH, the median survival period is almost 5 years.4 The median survival time of 1.9 years seen in patients with MCL treated with fludarabine is somewhat shorter than given in previous reports2,6,21; however, this is a small number of patients with advanced-stage disease, and the difference is probably not clinically significant. Toxicity was related mostly to myelosuppression and infection. The treatment-related mortality in this series was relatively high (5%) but similar to that of patients with WM receiving fludarabine in the Southwest Oncology Group trial (5%).27 The myelosuppressive and immunosuppressive toxicity is obviously of concern. More than 90% of patients presented with bone marrow involvement; it is possible that the myelosuppressive effects of fludarabine are greater in that setting. In future, such patients may benefit from prophylactic antibiotics or from prophylactic cytokine support (eg, granulocyte or granulocyte-macrophage colony-stimulating factor). The use of corticosteroids in this trial did not correlate with severe infection, although the number of patients and the degree of exposure were small (most were brief courses). Most patients respond to F-AMP after two to three cycles of therapy; in view of F-AMP's toxicity, it would be prudent to continue treatment beyond this point only in patients with responsive disease. Neurotoxicity has been reported in association with fludarabine, although usually when it is given at much higher doses or by continuous infusion13,32,33; many patients in this study developed nonspecific neurologic symptoms, such as asthenia or lethargy. However, significant neuropathy was not seen at this dose and schedule. Fludarabine has also recently been associated with the development of secondary myelodysplasia without classical cytogenetic changes34; to date, this has not been seen in the patients in this study. The role of additional cytotoxic therapy and irradiation confounds this association, inasmuch as myelodysplasia has also been seen in the context of high-dose therapy after treatment with fludarabine.35 Thus, further study is needed to confirm this observation. Exciting results have been presented about fludarabine in combination with other drugs in the treatment of follicular lymphoma. Fludarabine combined with mitoxantrone in patients with previously treated, low-grade NHL36-38 or combined with cyclophosphamide in patients with newly diagnosed disease39,40 has demonstrated high overall and complete response rates. In recurrent immunocytoma, overall and complete response rates of 83% and 55%, respectively, have recently been reported with fludarabine and mitoxantrone.41 A consecutive phase II trial of fludarabine, first as a single agent and then in combination with mitoxantrone, has shown an improved response rate for the latter regimen (42%) over fludarabine alone (31%) in patients with relapsed low-grade NHL.42 Furthermore, in patients with FL, these combinations have also been associated with the attainment of molecular remission.43 These preliminary data suggest that such an approach may be more widely applicable. Patients with LPC lymphoma, WM, and MCL remain a challenging management problem for clinicians; those with advanced-stage disease are demonstrably incurable. Fludarabine phosphate is an active drug and is an appropriate treatment option for some patients. Further studies are awaited to determine whether its inclusion in combination chemotherapy will improve the long-term outlook for such patients.
We gratefully acknowledge the physicians who referred patients for treatment, the help of diagnostic hematologists and radiologists at the participating centers, and the medical and nursing staff who helped care for these patients.
1. Galton DAG, Israels LG, Nabarro JDN, et al: Clinical trial of p (di-chloroethylamino) phenylbutyric acid (CB 1348) in malignant lymphoma. BMJ 2:1172, 1955 2. Brittinger G, Bartels H, Common H, et al: Clinical and prognostic relevance of the Kiel classification of non-Hodgkin's lymphomas: Results of a prospective multicenter study by the Kiel Lymphoma Study Group. Hematol Oncol 2:269-306, 1984[Medline] 3. Richards MA, Hall PA, Gregory WM, et al: Lymphoplasmacytoid and small cell centrocytic non-Hodgkin's lymphoma: A retrospective analysis from St. Bartholomew's Hospital 1972-1986. Hematol Oncol 7:19-35, 1989[Medline] 4. Papamichael D, Rohatiner AZS, Mulatero C, et al: Lymphoplasmacytoid lymphoma: A retrospective analysis from St. Bartholomew's Hospital 1972-96. Proc Am Soc Clin Oncol 16:17A, 1997 (abstr 57)
5.
Dimopoulos MA, Alexanian R: Waldenstrom's macroglobulinemia. Blood 83:1452-1459, 1994
6.
Norton AJ, Matthews J, Pappa V, et al: Mantle cell lymphoma: Natural history defined in a serially biopsied population over a 20 year period. Ann Oncol 6:249-256, 1995
7.
Gallagher CJ, Gregory WM, Jones AE, et al: Follicular lymphoma: Prognostic factors for response and survival. J Clin Oncol 4:1470-1480, 1986 8. DeVita VT, Canellos GP, Chabner B, et al: Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1:248, 1975[Medline]
9.
Fisher RI, Gaynor ER, Dahlberg S, et al: Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med 328:1002-1006, 1993 10. Lister TA, Cullen MH, Beard MEJ, et al: Comparison of combined and single-agent chemotherapy in non-Hodgkin's lymphoma of favorable histological sub-type. BMJ 1:533-537, 1978 11. Dana BW, Dahlberg S, Nathwani BN, et al: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol 11:644-651, 1993[Abstract] 12. Adkins JC, Peters DH, Markham A: Fludarabine: An update of its pharmacology and use in the treatment of haematological malignancies. Drugs 53:1005-1037, 1997[Medline] 13. Warrell RP, Berman E: Phase I and II study of fludarabine phosphate in leukemia: Therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol 4:74-79, 1986[Abstract]
14.
Keating MJ, Kantarjian H, Talpaz M, et al: Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74:19-25, 1989 15. Hochster HS, Kim K, Green MD, et al: Activity of fludarabine in previously-treated non-Hodgkin's low-grade lymphoma: Results of an Eastern Cooperative Oncology Group study. J Clin Oncol 10:28-32, 1992[Abstract] 16. Hiddemann W, Unterhalt M, Pott C, et al: Fludarabine single-agent therapy for relapsed low-grade non-Hodgkin's lymphoma: A phase II study of the German low-grade non-Hodgkin's lymphoma study group. Semin Oncol 20:28-31, 1993 (suppl 7) 17. Pigaditou A, Rohatiner AZS, Whelan JS, et al: Fludarabine in low-grade lymphoma. Semin Oncol 20:24-27, 1993 (suppl 7) [Medline]
18.
Zinzani PL, Lauria F, Rondelli D, et al: Fludarabine: An active agent in the treatment of previously-treated and untreated low-grade non-Hodgkin's lymphoma. Ann Oncol 4:575-578, 1993
19.
Solal-Celigny P, Brice P, Brousse N, et al: Phase II trial of fludarabine monophosphate as first-line therapy in patients with advanced follicular lymphoma: A multicenter study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 14:514-519, 1996 20. Stansfeld AG, Diebold J, Noel H, et al: Updated Kiel classification for lymphomas. Lancet 1:292-293, 1988 (letter) [Medline]
21.
Berger F, Felman P, Sonet A, et al: Nonfollicular small B-cell lymphomas: An heterogeneous group of patients with distinct clinical features and outcome. Blood 83:2829-2835, 1994
22.
Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361-1392, 1994 23. Harris NL, Bhan AK: B cell neoplasms of the lymphocytic, lymphoplasmacytoid and plasma cell types: Immunohistologic analysis and clinical correlation. Hum Pathol 16:829-837, 1985[Medline] 24. Shivdasani R, Hess JL, Skarin AT, et al: Intermediate lymphocytic lymphoma: Clinical and pathologic features of a recently characterized subtype of non-Hodgkin's lymphoma. J Clin Oncol 11:802-811, 1993[Abstract] 25. Kaplan ES, Meier P. Non-parametric estimation from incomplete observation. Am Stat Assoc J 53:457-480, 1958
26.
Dimopoulos MA, Kantarjian H, Weber D, et al: Primary therapy of Waldenstrom's macroglobulinemia with 2-chlorodeoxyadenosine. J Clin Oncol 12:2694-2698, 1994 27. Dhodapkar M, Jacobson J, Gertz M, et al: Phase II intergroup trial of fludarabine in Waldenstrom's macroglobulinemia: Results of a South Western Oncology Group trial 9003 in 220 patients. Proc Am Soc Hem 90:577a, 1997 (abstr) 28. Meusers P, Engelhard M, Bartels H, et al: Multicentre randomized therapeutic trial for advanced centrocytic lymphoma: Anthracycline does not improve the prognosis. Hematol Oncol 7:365-380, 1989[Medline] 29. Hiddemann W, Brittinger G, Tiemann M, et al: Clinical characteristics and response to chemotherapy of mantle cell lymphomas: Results of a European survey. Proc Am Soc Hem 88:674a, 1996 (abstr) 30. Decaudin D, Bosq J, Tertian G, et al: Phase II trial of fludarabine monophosphate in patients with mantle cell lymphoma. J Clin Oncol 16:579-583, 1998[Abstract] 31. Dimopoulos MA, O'Brien S, Kantarjian H, et al: Fludarabine therapy of Waldenstrom's macroglobulinemia. Am J Med 95:49-52, 1993[Medline] 32. Johnson PWM, Fearnley J, Domizio P, et al: Neurological illness following treatment with fludarabine. Br J Cancer 70:966-968, 1994[Medline]
33.
Cheson BD, Vena DA, Foss FM, et al: Neurotoxicity of purine analogs: A review. J Clin Oncol 12:2216-2228, 1994 34. Orchard JA, Bolam S, Oscier DG: Association of myelodysplastic changes with purine analogues. Br J Haematol 100:677-679, 1998[Medline] 35. Ketterer N, Salles G, Dumontet C, et al: Fludarabine may increase the toxicity of peripheral blood progenitor cell transplantation. Proceedings of the Internatial Society of Hematology-European Hematology Association Combined Congress, Amsterdam, the Netherlands, July 4-8, 1998. Br J Haematol 102:204a, 1998 (abstr) 36. McLaughlin P, Hagemeister FB, Swan F Jr,et al: Phase I study of fludarabine, mitoxantrone and dexamethasone in low-grade lymphoma. J Clin Oncol 12:575-579, 1994[Abstract] 37. McLaughlin P, Hagemeister FB, Romaguera JE, et al: Fludarabine, mitoxantrone and dexamethasone: An effective new regimen for indolent lymphoma. J Clin Oncol 1262-1268, 1996 38. Zinzani PL, Bendandi M, Tura S: FMP regimen (fludarabine, mitoxantrone, prednisone) as therapy in recurrent low-grade non-Hodgkin's lymphoma. Eur J Haematol 55:262-266, 1995[Medline] 39. Klasa R, Connors J, Gascoyne R, et al: CPF (cyclophosphamide, prednisone, fludarabine) in advanced stage previously untreated low-grade and mantle cell lymphoma. Proc Am Soc Hem 90:342a, 1997 (abstr) 40. Hochster H, Oken M, Bennett J, et al: Efficacy of cyclophosphamide and fludarabine as first line therapy of low-grade non-Hodgkin's lymphoma-ECOG 1491. Proc Am Soc Hem 84:383a, 1994 (abstr)
41.
Zinzani PL, Bendandi M, Magagnoli M, et al: Fludarabine-mitoxantrone combination-containing regimen in recurrent low-grade non-Hodgkin's lymphoma. Ann Oncol 8:379-383, 1997 42. Pott C, Unterhalt M, Sandford D, et al: Fludarabine as single agent and in combination with mitoxantrone and dexamethasone in relapsed and refractory low-grade non-Hodgkin's lymphoma. Ann Haematol 68:A2, 1994 (suppl 1) 43. McLaughlin P, Cabanillas F, Younes A, et al: Stage IV low-grade lymphoma: Randomized trial of two innovative regimens, with monitoring of Bcl-2 by PCR. Proceedings of the VI Internatioal Conference on Malignant Lymphoma. Ann Oncol 7:A109, 1996 (suppl 3) Submitted July 2, 1998; accepted October 6, 1998.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70%. The majority of patients with WM presented with bone marrow involvement only. 
