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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From Département d'hématologie,
Hôpital Pitié-Salpétrière, AP-HP, Paris;
Département de biostatistique et informatique médicale,
Hôpital Saint-Louis, U 444 INSERM, Paris; Centre
Hospitalier Régional Universitaire, Hôpital Hautepierre,
Strasbourg; Centre Hospitalier Régional Universitaire,
Hôpital Claude Huriez, Lille; Service
d'immuno-hématologie, Hôpital Saint-Louis, AP-HP
Paris; Centre Hospitalier Universitaire, Hôtel-Dieu, Nantes;
Centre Hospitalier Universitaire, Limoges; Centre Hospitalier
Universitaire, Angers; Centre Hospitalier Universitaire, Bordeaux;
Centre Hospitalier Universitaire, Besançon; Centre Hospitalier
Universitaire, Amiens; Centre Hospitalier Universitaire, Poitiers;
Centre Hospitalier, Pontoise; Centre anti-cancéreux Becquerel,
Rouen; and Laboratoire Schering, Lys-lez-Lannoy, France.
Few reports are available on the treatment of patients with
Waldenström macroglobulinemia (WM) and primary or secondary
resistance to alkylating-agent-based regimens. From December 1993 through December 1997, 92 patients with WM resistant to first-line
therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m2 of
body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m2
cyclophosphamide and 25 mg/m2 doxorubicin on day 1 and 40 mg/m2 prednisone on days 1-5). The first end point
evaluated was the response rate after 6 treatment courses. Forty-five
patients received CAP and 45 received fludarabine. Two patients died
before the first course of chemotherapy. No statistical differences
were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P = .019). Responses were more
durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in
this group (P < .01). Forty-four patients died, 22 in
the fludarabine group and 22 in the CAP group. There was no statistical
difference in the median overall survival time in the 2 study arms.
Fludarabine was thus more active than CAP in salvage therapy of WM and
should be tested as first-line therapy in a randomized comparison with alkylating agents.
(Blood. 2001;98:2640-2644) Waldenström macroglobulinemia (WM)
results from malignant proliferation of well-differentiated plasmacytic
lymphocytes that produce monoclonal IgM.1 According to the
revised European-American lymphoma classification of lymphoid
neoplasms, WM accounts for most diagnoses of lymphoplasmacytoid
lymphoma/immunocytoma.2 WM is characterized by a highly
variable clinical picture, with complications being determined by the
physicochemical properties and antibody activity of the monoclonal
IgM.3,4 Chemotherapy with alkylating agents alone or
combined with corticosteroids has been the standard primary treatment
for patients with symptomatic macroglobulinemia. The agent most
commonly employed is oral chlorambucil, which is used in both daily
low-dose schedules and intermittent high-dose
schedules.3,5,6 Others7,8 have used
combinations of alkylating agents given with or without a vinca
alkaloid or nitrosurea, but there is no evidence that such combinations
are more beneficial.
Preliminary studies suggested that purine analogs such as fludarabine
and 2-chlorodeoxyadenosine (2-CdA) are effective in most patients with
WM. Approximately 50% of previously untreated patients have a response
to conventional therapies, whereas more than 75% of patients may
respond to nucleoside analogs.9-15 The few available
reports on treatment of patients with primary or secondary resistance
to first-line therapies showed a benefit with
interferon,16,17 doxorubicin,18 and
nucleoside analogs. Kantarjian et al,14 Dimopoulos et
al,19 and Zinzani et al20 reported responses
to fludarabine salvage therapy in about one third of patients with
resistance to previously administered treatments, and these
results were confirmed by other studies. We previously reported a
series of 71 patients with advanced and resistant WM in whom
fludarabine yielded a 30% response rate and a median overall survival
time of 23 months; unfortunately, toxicity was severe in these heavily
pretreated patients.21 Here, we describe a randomized,
multicenter study comparing the efficacy of fludarabine with that of
the combination of cyclophosphamide, doxorubicin (Adriamycin), and
prednisone (CAP) in 92 WM patients with first relapse or primary
refractory disease.
Patients and treatment
Patients were randomly assigned to receive fludarabine (25 mg/m2 of body-surface area given intravenously during 30 minutes daily for 5 consecutive days) or CAP (750 mg/m2
cyclophosphamide and 25 mg/m2 doxorubicin given
intravenously on day 1, and 40 mg/m2 prednisone given
orally on days 1-5). Treatment courses were repeated every 4 weeks,
with a target of 6 courses. Oral trimethoprim-sulfamethoxazole (200 mg/day and 40 mg/day) or pentamidine aerosols (300 mg once a month) and
oral acyclovir (800 mg/day) were given to patients treated with
fludarabine to prevent Pneumocystis carinii and herpesvirus infection, respectively, during all courses of chemotherapy.
Evaluation of responses
Assessment of adverse effects All patients were included in the evaluation of adverse effects, and toxicity was analyzed according to World Health Organization criteria. Hematologic values and other clinical and laboratory indicators of adverse effects were recorded at least monthly by the data-management office and were reported at each round of treatment.Statistical analysis The cut-off date for this analysis was April 15, 2000. Results were assessed on an intent-to-treat basis. The primary end point was the response after 6 treatment courses. The sample size was computed in 88 patients per group on the basis of an expected intergroup difference in response rate of 25% (25% with CAP and 50% with fludarabine), a type 1 error of 5%, a power of 90%, and an interim analysis after enrollment of half of the 196 patients. The trial was stopped after the interim analysis. Other end points were the response after 3 courses, event-free survival (EFS) rate, duration of response, and overall survival (OS) rate. EFS was measured from enrollment to disease progression, death from any cause, or the date of the last follow-up visit. Duration of response was measured from the date of response to disease progression or death, only in responding patients. OS was measured from enrollment to death or the last follow-up visit. Survival curves for EFS and OS in the 2 treatment groups were plotted by using the Kaplan-Meier method and compared by using the log rank test.22 All analyses were done with SAS (SAS Institute, Cary, NC) and Splus software (Mathsoft, Seattle, WA).
Responses and survival Forty-six patients were randomly assigned to each arm, and 45 patients in each arm received the first round of chemotherapy. There were 50 patients with first relapse and 42 with primary resistant disease. Clinical and biologic characteristics of the patients in the 2 treatment groups are shown in Table 2. There were no significant differences between the groups in clinical disease manifestations, duration of previous treatment, or disease status at enrollment. The only significant biologic differences between the 2 groups were in their hemoglobin and C-reactive protein levels. One patient in each arm died before the first round of chemotherapy.
Treatment response could be assessed in 90 patients. A partial response
was observed after 3 courses of treatment in 3 of 45 patients treated
with fludarabine and 2 of 45 patients treated with CAP. After 6 courses, 14 patients (30%) treated with fludarabine and 5 patients
(11%) patients treated with CAP had a partial response (P=.02). No complete remissions were observed in either
group. The median duration of response was 19 months after fludarabine therapy and 3 months after CAP therapy (P < .01). EFS was
significantly higher in patients treated with fludarabine
(P < .01; Figure 1). The
median follow-up time among survivors was 52 months (range, 29 to
86 months).
Forty-four patients died, 22 in the fludarabine group and 22 in the CAP
group. The median survival time was 41 months in patients treated with
fludarabine and 45 months in those treated with CAP (P not
significant). The OS rate was similar in the 2 groups (Figure 2). The causes of death are listed in
Table 3. Eight patients in the
fludarabine group and 14 in the CAP group died from disease progression. Four cases of secondary acute myeloid
leukemia/myelodysplastic syndrome (AML/MDS) and 3 cases of disease
transformation into diffuse large-cell lymphoma (Richter syndrome)
occurred in the fludarabine group, and 2 cases of secondary AML/MDS and
2 cases of disease transformation into diffuse large-cell lymphoma
occurred in the CAP group.
Adverse effects There were no significant differences between the 2 treatment groups in hematologic toxicity. Mucositis and alopecia occurred significantly more often in patients treated with 25 mg/m2 doxorubicin in the CAP regimen, with 10 episodes of grade 1 or higher mucositis. We did not observe any instance of grade 1 mucositis or higher in patients treated with fludarabine. Eleven patients treated with CAP and 3 treated with fludarabine had grade 1 or higher alopecia. The frequency and severity of infections were identical in the 2 groups (Table 4). A quality-of-life study based on quality-adjusted time without symptoms or toxicity was reported previously.23
Salvage treatment of patients with WM and primary or secondary resistance to first-line therapy has not previously been studied in a randomized trial. During the past decade, the newer nucleoside analogs (2-CdA and fludarabine) have shown activity in this setting, even in patients with resistant disease. Studies found that 2-CdA yielded a high response rate (75%) in untreated patients with WM, although few complete remissions were observed.14,24,25 Fludarabine has also been studied as front-line treatment of WM: a European multicenter phase II study of 20 previously untreated patients with WM showed objective responses in 79%, with a median time to disease progression of 40 months.15 However, the response rate was lower in a preliminary study by Dhodapkar et al,26 with only 33% of responses occurring in previously untreated patients. Approximately one third of previously treated patients are expected to have an objective response to purine nucleoside analogs.10,12,13,25 We recently reported a retrospective study of 71 patients with advanced disease treated with fludarabine.21 As in previous studies, 30% of patients had a response, and the median survival time among such patients was 30 months. Unfortunately, toxicity was severe, with 5 deaths due to infection after only 1 or 2 courses of treatment and 2 deaths from infection in patients with a response. The median survival time in the entire group was 23 months. We thus conducted a randomized study to test the efficacy of
fludarabine in patients with primary resistance or first relapse after
alkylating-agent-based regimens. The upper age limit of 75 years was
chosen because of the high toxicity rate associated with fludarabine in
heavily pretreated patients in our previous study.21 As in
the largest reported series, a monoclonal IgM component of at
least 5 g/L on electrophoresis study was chosen as the cut-off value
for inclusion in the study.27-29 Previous trials of
second-line treatments involved doxorubicin, high-dose corticosteroids,
Our prospective study found that fludarabine was significantly more effective than CAP, on the basis of the number and duration of responses and the EFS rate. However, the median survival time was similar in the 2 treatment groups. This not the first trial to show no difference in survival rates among patients with chronic lymphoproliferative disorders, even with a large number of patients. Rai et al34 reported a randomized trial in patients with chronic lymphocytic leukemia in whom the response rate and median duration of remission were better in the group given fludarabine but the survival rate was not, despite enrollment of 178 patients in the fludarabine group. Similar results were observed in a trial that tested the efficacy of 2-CdA and prednisone compared with chlorambucil.35 The lack of difference in OS rate in our study might be explained by efficient salvage treatment after relapse. It was not due to treatment switches after failure of the regimen to which patients had been randomly assigned: only 10 patients in the CAP group received fludarabine and only 1 had a response; likewise, 5 patients with no response to fludarabine received CAP, and only 1 had a response. Thus, the lack of any difference in OS rate between the 2 groups seems rather to have been due to the higher rate of deaths unrelated to disease progression in the fludarabine group, in which 4 patients died from myocardial infarction, 1 from myocardial infarction, 1 from lung cancer, 1 from a trauma-related pulmonary complication, and 1 from acute graft-versus-host disease after allogeneic bone marrow transplantation. Tolerability was good, but mucositis and alopecia occurred more frequently with the 25 mg/m2 dose of doxorubicin in the CAP regimen. Few patients had severe infections during treatment, and there was no significant difference between the 2 treatment groups in progression to higher-grade lymphomas such as large-cell immunoblastic lymphoma, a finding that confirmed, in this randomized study, the data of Cheson et al,36 who found no significantly increased risk of secondary malignant disease in patients treated with nucleoside analogs. Dimopoulos et al19,24 found that disease status at the outset of salvage treatment with a nucleoside analog was a predictor of the likelihood and durability of responses. Although we administered salvage treatment early in the disease course, we did not obtain a higher response rate than in our previous study, which included 63 patients with refractory relapse and 8 patients with primary refractory disease. However, the median OS time in the current trial (45 months) was longer than that in the previous study (23 months). These results suggest that treatment with nucleoside analogs should be started without delay in patients with macroglobulinemia and first relapse or primary resistance to alkylating agents. The efficacy of fludarabine used as first-line therapy is controversial.15,26 These results have prompted establishment of a European multicenter trial comparing the efficacy of fludarabine with that of chlorambucil in untreated patients. Patients with resistance to nucleoside analogs need new therapeutic strategies, such as anti-CD20 monoclonal antibodies, which may be active in about 30% of previously treated patients.37,38 Factors indicating a poor prognosis at diagnosis of WM were described by Facon et al27 and Morel et al,28 who defined subgroups of WM patients with significantly different survival rates on the basis of age, albumin level, and severity of cytopenia. High-risk patients had a 5-year survival rate of 27%. Furthermore, resistance to first-line therapy with alkylating-agent-based regimens was shown to have an adverse effect on survival.3,5,27 Thus, young patients with indicators of a poor prognosis at diagnosis or who have resistance to first-line therapy (including some with resistance to nucleoside analogs) might benefit from high-dose therapy with autologous stem-cell rescue used early during the disease course.39-41
Submitted August 29, 2000; accepted June 16, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Véronique Leblond, Département d'hématologie, Hôpital Pitié-Salpêtrière, 47 boulevard de l'Hôpital, 75013 Paris, France; e-mail: veronique.leblond{at}psl.ap-hop-paris.fr.
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1999;17:2454-2460 37. Weber DM, Gavino M, Huh Y, Cabanillas F, Alexanian R. Phenotypic and clinical evidence supports rituximab for Waldenström's macroglobulinemia [abstract]. Blood. 1999;94:125a. 38. Weide R, Heymanns J, Koppler H. Induction of complete hematological remission after monotherapy with anti-CD20 monoclonal antibody (Rituximab) in a patient with alkylating agent resistant Waldenström's macroglobulinemia. Leuk Lymphoma. 1999;36:203-206[Medline] [Order article via Infotrieve]. 39. Yang L, Wen B, Li H, et al. Autologous peripheral blood stem cell transplantation for Waldenström's macroglobulinemia. Bone Marrow Transplant. 1999;24:929-930[CrossRef][Medline] [Order article via Infotrieve]. 40. Desikan R, Dhodapkar M, Siegel D, et al. High-dose therapy with autologous haematopoietic stem cell support for Waldenström's macroglobulinaemia. Br J Haematol. 1999;105:993-996[CrossRef][Medline] [Order article via Infotrieve]. 41. Dreger P, Glass B, Kuse R, et al. Myeloablative radiochemotherapy followed by reinfusion of purged autologous stem cells for Waldenström's macroglobulinaemia. Br J Haematol. 1999;106:115-118[CrossRef][Medline] [Order article via Infotrieve].
The following departments of hematology of the French Cooperative Group on Chronic Lymphocytic Leukemia and Macroglobulinemia participated actively in this study. The number of patients enrolled is indicated in parentheses: Centre Hospitalier Universitaire, Strasbourg: F. Maloisel (9); Centre Hospitalier Universitaire, Lille: B. Cazin (5); Hôpital Saint-Louis, Paris: J. P. Fermand (5); Centre Hospitalier Universitaire-Hotel Dieu, Nantes: J. L. Harousseau (5); Hôpital Pitié-Salpétrière, Paris: V. Leblond (5); Centre Hospitalier Universitaire, Limoges: L. Remeneiras (5); Centre Hospitalier Universitaire, Angers: M. Gardembas (4); Centre Hospitalier Universitaire, Besançon: E. Deconinck (4); Centre Hospitalier Universitaire, Pessac: G. Marit (4); Centre Hospitalier, Amiens: B. Desablens (3); Centre Hospitalier Universitaire, Poitiers: F. Guilhot (3); Centre Hospitalier, Pontoise: G. Philippe (3); Centre anti-cancéreux Becquerel, Rouen: A. Stamatoullas (3); Centre Hospitalier, Suresnes: A. Baumelou (2); Hôpital Necker, Paris: C. Bélanger (2); Hôpital Saint-Louis, Paris: J. P. Clauvel (2); Hôpital Henri Mondor, Créteil: M. Divine (2); Centre Hospitalier, Nancy: N. Feugier (2); Centre Hospitalier, Martigues: M. Nezri (2); Hôpital Kremlin-Bicêtre, Kremlin: G. Tertian (2); Centre anti-cancéreux Lacassagne, Nice: A. Thyss (2); Centre Hospitalier, Avignon: A. M. Touchais (2); Hôpital Saint-Louis, Paris: P. Brice (1); Centre Hospitalier, Briis sous Forge: N. Cheron (1); Hôpital Hotel-Dieu, Paris: A. Delmer (1); Centre Hospitalier, Troyes: G. Dine (1); Institut Bergonie-CRLCC, Bordeaux: H. Eghbali (1); Centre Hospitalier Universitaire, Lyon: D. Fière (1); Centre Hospitalier Dr Schaffner, Lens: P. Morel (1); Hôpital Percy, Clamart: G. Nedelec (1); Centre Hospitalier, Valenciennes: J. P. Pollet (1); Hôpital Charles-Foix, Ivry: O. Saint-Jean (1); Clinique Victor Hugo, Le Mans: P. Solal-Celigny (1); Centre Hospitalier, Clermont-Ferrand: P. Travade (1); Centre Hospitalier, Caen: X. Troussard (1); Hôpital Beaujon, Clichy: P. Turlure (1); and Centre Hospitalier, Compiègne: D. Zylberait (1). Also participating was Laboratoire Schering, Lys Lez Lannoy: O. Guibon. The coordinating center was Hôpital Pitié-Salpétrière, Paris: V. Leblond. The statistical center was Département de biostatistique et informatique médicale, Hôpital Saint-Louis, Paris: V. Lévy and R. Porcher.
© 2001 by The American Society of Hematology.
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  A. Vijay and M. A. Gertz Waldenstrom macroglobulinemia Blood, June 15, 2007; 109(12): 5096 - 5103. [Abstract] [Full Text] [PDF]
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 C. I. Chen, C. T. Kouroukis, D. White, M. Voralia, E. Stadtmauer, A. K. Stewart, J. J. Wright, J. Powers, W. Walsh, and E. Eisenhauer Bortezomib Is Active in Patients With Untreated or Relapsed Waldenstrom's Macroglobulinemia: A Phase II Study of the National Cancer Institute of Canada Clinical Trials Group J. Clin. Oncol., April 20, 2007; 25(12): 1570 - 1575. [Abstract] [Full Text] [PDF]
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M. A. Dimopoulos, R. A. Kyle, A. Anagnostopoulos, and S. P. Treon Diagnosis and Management of Waldenstrom's Macroglobulinemia J. Clin. Oncol., March 1, 2005; 23(7): 1564 - 1577. [Abstract] [Full Text] [PDF]
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 C. I. Chen Treatment for Waldenstrom's macroglobulinemia Ann. Onc., April 1, 2004; 15(4): 550 - 558. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
2 microglobulin, and C-reactive protein. Bone marrow
aspirates or bone marrow trephine biopsy samples were obtained to
determine the percentage of lymphocytes, lymphocytoid plasma cells, and plasma cells. The response criteria were adapted from those used for
multiple myeloma and from previous studies of WM. A partial response
was defined as a sustained decrease of more than 50% in the IgM
production rate (on densitometry tracing of the serum electrophoretic
pattern) on at least 2 occasions 2 months apart and a more than 50%
reduction in the size of all involved organs. A complete response was
defined as disappearance of the monoclonal IgM (on immunofixation
study), resolution of lymphadenopathy and splenomegaly, and a finding
of less than 20% lymphocytes in the bone marrow. Patients with a
response were subsequently monitored without treatment until disease
progression, defined as a more than 25% increase in tumor mass
relative to the lowest level achieved. Treatment was considered to have
failed in patients with a mixed response, no response, or withdrawal
from the trial for any reason.
interferon, and splenectomy, but these studies were limited and the
results not particularly noteworthy.
a new syndrome?
Acta Med Scand.
1944;117:216-247.
-interferon (