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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Laboratory of Cellular Physiology and
Immunology, Rockefeller University, New York, NY; Southwest Oncology
Group Statistical Center, Seattle, WA; Mayo Clinic, Rochester, MN;
Puget Sound Oncology Consortium, Seattle, WA; University of Texas
Health Science Center at San Antonio; University of California, Davis,
Sacramento; Henry Ford Hospital, Detroit, MI; and University of
Arkansas for Medical Science, Little Rock.
Current information on Waldenström macroglobulinemia (WM) is
based on retrospective or single-institution studies of patients requiring therapy. Between 1992 and 1998, 231 patients with WM were
enrolled in a prospective observational multicenter clinical trial. Of
these, 182 patients with symptomatic or progressive disease were
treated with 4 to 8 cycles of therapy with a purine nucleoside
analogue, fludarabine (FAMP; 30 mg/m2 of body-surface area
daily for 5 days every 28 days). A serum The term Waldenström macroglobulinemia
(WM) was originally coined to describe a clinical syndrome
characterized by high levels of macroglobulin (IgM) and symptoms
related to hyperviscosity or lymphocytoid tissue
infiltration.1 Histologically, the disease overlaps with
lymphoplasmacytoid lymphoma or immunocytoma in the Kiel classification
and lymphoplasmacytic lymphoma in the World Health Organization
classification.2 Although most patients present with
symptomatic disease, WM is often diagnosed during the asymptomatic
stage.3 Care of patients with WM remains a challenge
because current information on its natural history, therapy, and
prognosis is limited to data derived from small retrospective or
single-institution studies.3-5 Moreover, these studies
focused largely on patients who required therapy. The decision to
initiate therapy is therefore generally individualized. Survival and
disease progression after therapy are difficult to predict, and no
standard prognostic models exist.3 Low-dose chlorambucil
is the mainstay of therapy but rarely produces complete remissions
(CRs).6,7 Purine analogs such as fludarabine phosphate
(FAMP) and 2-chlorodeoxyadenosine (2-CDA) have shown remarkable
activity in low-grade lymphoproliferative disorders.8 In
small preliminary studies, promising clinical activity of both FAMP and
2-CDA in WM was observed.8-15
In 1992, the Southwest Oncology Group (SWOG) began a prospective
clinical trial to examine the natural history of WM and evaluate the
clinical activity of FAMP in untreated patients as well as those who
had previously undergone alkylating agent-based therapy. We present
the results of this first large intergroup clinical trial in patients
with WM. We also describe a simple prognostic model predictive of the
need for therapy and of survival.
Eligibility and study design
In the absence of symptoms or advanced tumor mass, patients were
registered for observation after baseline studies were completed. Patients were eligible for registration for therapy with FAMP if
WM-related symptoms thought to require therapy developed or they had an
marked tumor mass defined as lymphadenopathy (> 2 cm), palpable
hepatomegaly, splenomegaly, or considerable (> 50%) bone marrow
infiltration. Patients were also eligible for therapy if they had
evidence of disease progression defined as an increase in serum IgM
level of at least 50% or a decrease in hemoglobin level of more than
20 g/L (2 g/dL) or in platelet count of more than
50 × 109/L (50 000/µL). In cases in which the
indications for therapy were clinically unclear, investigators were
encouraged to observe the patients to obtain information on disease
evolution. Patients meeting the criteria for therapy at initial
registration were eligible for immediate reregistration for therapy.
Patients were stratified at the time of treatment according to whether
they had previously received therapy for WM.
Treatment
Laboratory monitoring
Response criteria CR required the disappearance of all monoclonal protein in the serum or urine on immunofixation studies and resolution of measurable tumor mass lesions and marrow involvement for at least 2 months. Remission (R) required at least a 75% reduction in IgM levels together with at least a 50% reduction in tumor mass lesions and a decrease in marrow lymphocytosis to below 25%. Partial remission (PR) was defined as a greater than 50% reduction in IgM level and tumor mass lesions. All responses had to be confirmed by a second assessment 4 weeks later. Progression was defined as an increase in measurable tumor marker lesions of more than 25% after 2 cycles of FAMP.Statistical analysis Overall survival (OS) from initial or treatment registration was calculated as time from registration to the last date of contact or the date of death. Progression-free survival (PFS) was calculated as time from treatment registration to the date of progression, death, or last contact. Time to treatment was calculated as the time from initial registration to date of treatment registration (for patients who did not register concurrently to receive the treatment step). Survival curves were estimated by using the product limit method and compared by using the log rank test.17,18 Proportions were compared with the 2 test. Univariate and multivariate analyses
were done with the Cox regression model for survival and with logistic
regression for binary end points.19,20
To construct a prognostic model for patients with WM, the following
pretreatment factors were analyzed by using univariate Cox proportional
hazards regression: previous therapy, age at registration, patient sex,
hemoglobin, serum IgM, serum IgG, serum IgA, serum Potential prognostic factors were examined as both continuous variables and dichotomous groups. Only dichotomous variables were used to construct the prognostic models, since the goal was to use easily interpreted groupings. Recursive partitioning methods were used to calculate the best cut point (based on the log rank statistic) for continuous variables that were significant in the univariate models.21 Recursive partitioning methods are based on the raw data and compute cut points that provide the greatest separation in the outcome of interest. Because clinically relevant cut points for possible prognostic factors in WM have not been not defined and are often borrowed from accepted myeloma or lymphoma models, we used adaptive cut points when different from the standard (for example, age in years, 65 [standard] versus 70 [most significant]).
Clinical characteristics Between November 1992 and November 1998, 231 eligible patients with WM were enrolled in the study, 182 of whom required therapy with FAMP (Figure 2). Of these 182 patients, 118 had received no previous therapy and 64 had undergone treatment previously. Clinical and laboratory features at initial presentation in these cohorts are shown in Table 1 and Table 2, respectively. Even with the use of CT scanning of the abdomen at baseline, splenomegaly and lymphadenopathy were detected in only 17% and 19%, respectively, of the patients in these 2 groups. Serum 2M was elevated at least 3 mg/L in 50% of the patients. Most of the patients (66%) were entered
into the study within a year of diagnosis. Among the previously treated
patients, the earlier therapy consisted of administration of alkylating
agents in all except 4 patients (one who had received plasmapheresis, 1 dexamethasone, and 2 of whom had a response to cladribine).
Analysis of cohort not requiring therapy One hundred sixty-five patients were reregistered immediately (or within 2 weeks) for the treatment step because of symptomatic or progressive disease. Fifty-four patients were observed without therapy for more than a year (median follow-up, 44 months; range, 16-88 months). A comparison of clinical features in this observation cohort with those in the cohort requiring therapy immediately or within a year revealed a significantly (all P < .05) lower incidence of anemia (hemoglobin level < 120 g/L [12 g/dL]), thrombocytopenia (platelet count < 150 × 109/L [150 000/µL]), lymphadenopathy, hepatosplenomegaly, hypoalbuminemia (albumin level, < 35 g/L [3.5 g/dL]), and serum hyperviscosity. In addition, the cohort not requiring therapy also had a lower proportion of patients with elevated levels of serum IgM ( 40 g/L [4 g/dL]), CRP ( 1.0 mg/L),
and 2M ( 3 mg/L; all P < .05; Tables 1 and
2).
Analysis of factors predicting requirement for therapy On multivariate analysis, hemoglobin and serum2M levels at
presentation were the only significant predictors of an eventual need
for therapy in the 66 patients who did not immediately register for
therapy. Serum 2M levels below 3 mg/L and hemoglobin levels of at
least 120 g/L identified a subset of patients with the lowest probability of requiring therapy. Thirty-seven of the 66 patients who
did not immediately register for therapy were in this subset, and only
5 of these 37 eventually registered for therapy. Patients with serum
2M levels of 3 mg/L or higher or hemoglobin levels below 120 g/L
were overall 2.4 times more likely to require therapy (P = .02).
Response to FAMP Response was assessed in all 182 eligible patients with a median follow-up of 30 months. The overall confirmed response rate to FAMP therapy was 36% (95% confidence interval [CI], 29%-44%), with 4 CRs (2%), 25 remissions (14%), and 34 PRs (19%) (Table 3). Unconfirmed partial responses (failure to have a second assessment 4 weeks after the initial response) were observed in 3 additional patients (2%). Response to therapy was not significantly greater in the cohort with no previous therapy than in those previously given alkylating agent-based treatment (38% [95% CI, 29%-48%] versus 33% [95% CI, 22%-46%]; P = .62). CR was achieved in only 4 patients (4%) with no previous therapy, and no CRs were attained in previously treated patients. Most responses occurred within 3 to 6 months of initiation of therapy; however, delayed responses occurring more than 6 months and more than 1 year, respectively, after initiation of therapy were observed in 17% and 5% of patients with a response (data not shown).
Factors predicting response to FAMP Age at the time of registration was the only significant variable predicting response to treatment ( PR), both as a continuous and a
dichotomized variable. Patients older than 70 years had a substantially
lower response rate (hazard ratio (HR), 0.34; P = 0.004)
than younger patients. Age was also the only significant variable
predicting response in the cohort with no previous therapy (HR, 0.33, P = 0.02). No variables predicting CR or near CR (R and
CR) were identified.
Toxicity of FAMP therapy Toxicity had been assessed for 175 of the 182 patients at the time of the analysis described here. The principal toxic effect of FAMP was myelosuppression (Table 4), from which most patients recovered rapidly. Seven patients (4%) died as a result of possible treatment-related toxicity consisting of infection-related complications.
OS and PFS With a median follow-up of 41 months, 152 of 231 patients are alive, for an estimated 5-year OS rate of 58% (Figure 3A). Estimated rates of 5-year OS and PFS from treatment registration in the treated cohort were 50% and 41%, respectively (Figure 3B and 3C). The 5-year rates of OS and PFS in the cohort with no previous therapy were 62% and 49%, respectively, whereas those in the previously treated patients were 36% and 30%, respectively.
Analysis of prognostic factors Predictors of OS in the entire cohort.
In univariate analysis, higher age and serum
2M, we evaluated each of the 4 groups (low and high
2M and IgM) individually. In the group with high 2M levels ( 3 mg/L), there was a large survival difference between patients in the
low-IgM group (< 40 g/L) and those in the high-IgM group (5-year OS,
51% versus 0%). However, in the low-2M group, there was little
difference in survival according to whether the serum IgM level was low
or high (5-year OS, 76% and 77%, respectively). Therefore, the
significance of IgM in the multivariate stepwise model appeared to
depend on the large survival difference between patients with low IgM
levels and those with high IgM levels in the high-2M group and was
lost when this group was excluded.
Diagnostic criteria for WM in previous studies were variable and
somewhat arbitrary.3 Specifically, existing data do not allow establishment of a clear cut-off point for serum IgM level and
percentage of marrow involvement. Pathological evaluation in WM is
complicated by the low concordance rate among pathologists for the
diagnosis of lymphoplasmacytic or lymphoplasmacytoid disorders in the
Revised European-American Lymphoma classification. The eligibility
criteria in this study therefore did not specify a minimal percentage
of marrow involvement and IgM level. However, the broad inclusion
criteria used in the study did raise the possibility of inclusion of
patients who might otherwise be considered to have IgM-monoclonal
gammopathy of undetermined significance (MGUS). In this data set, we
found only 5 asymptomatic patients with serum IgM levels below 30 g/L,
marrow lymphocytosis below 20%, and no lymphadenopathy and
hepatosplenomegaly, a condition that could be classified as
IgM-MGUS.5 These patients did not require therapy, and
their exclusion did not significantly affect any survival analysis.
Predictors of survival and disease progression in patients treated
with FAMP.
In the univariate analysis of patients treated with FAMP, age 70 years
or older, previous treatment, disease duration greater than a year, CRP
of 1.0 mg/L or higher, serum IgM level below 40 g/L, and serum Development of risk models Prognostic models that predict survival may not predict the risk of disease progression in treated patients (for example, the Rai classification in chronic lymphocytic leukemia [CLL]).22 Therefore, we examined risk models in the entire cohort and in the treated patients separately.Risk model in the entire cohort.
Serum
Risk model in patients treated with FAMP.
We used 2 significant prognostic variables, serum Development of a staging system Because the 2 risk models were remarkably similar, we combined them to develop a novel staging system for WM (Table 6). According to this model, patients with stage A disease (low risk) have an excellent prognosis and the lowest probability of requiring therapy, and they may include a subset with "smoldering macroglobulinemia." Patients with stages B to D generally require therapy but have a highly variable outcome after FAMP therapy. Those with stage B or C disease (intermediate risk) have similar OS but differ in durability of response after therapy (Table 6). In particular, patients with stage D disease (high risk) fare poorly. These patients also have a significantly higher incidence of anemia, hypoalbuminemia, lymphadenopathy, and hepatosplenomegaly than other patients (data not shown).
Management decisions in WM, a clinical syndrome with a highly
variable prognosis, are complicated by the lack of a standard prognostic model predicting the need for therapy and patient survival. In this study, we analyzed data from the first large prospective multicenter study of WM to describe the clinical response to a purine
analog (FAMP) and develop a simple staging system predictive of both
the need for therapy and the OS and PFS of patients. The clinical
characteristics and laboratory data at study entry in our patients were
comparable to those in previously reported
investigations.3,5 However, this study was the first in
which several laboratory characteristics, including serum This was also the first study in which patients with asymptomatic or
early macroglobulinemia were followed prospectively, and it therefore
provides insights into predictors of the need for therapy in such
patients. We found that low serum levels of The clinical activity of FAMP we observed in patients with WM who had previously been given alkylating agents was similar to that occurring in earlier small or retrospective studies.11,13,14 However, a lower proportion of previously untreated patients had a response than was observed in one small study.15 It should be stressed, however, that none of these studies are directly comparable with respect to clinical activity. Possible reasons for the difference include a small sample size (19 patients in one study) and differences in patient populations or response criteria. For example, the age distribution of patients or the need to confirm response after 4 weeks in the current study may have affected the observed response rate. Because most treated patients had a follow-up exceeding 1 year, however, it is unlikely that a failure to record delayed or mixed responses (for example, improvement in splenomegaly without a reduction in paraprotein levels) accounts for the observed results. Several other therapeutic approaches have been used in patients with
WM, including administration of another purine nucleoside analog,
2-CDA; alkylating agents, used either singly or in
combination23; steroids; Few studies have analyzed prognostic factors in patients with
WM.27-31All studies that did include such an analysis were
retrospective. Of the 3 larger studies, one found hypoalbuminemia, age,
and cytopenias to be independent predictors,28 whereas
another identified anemia, age, weight loss, and cryoglobulinemia as
prognostic factors.29 The third found that age, albumin
level, and the number of cytopenias were prognostically
important.31 In our study, age, anemia, and
hypoalbuminemia were significant factors in the univariate analysis,
but serum An important finding of our study is identification of serum Similarities among various risk models allowed us to develop a simple
staging system predictive of both the need for therapy and survival in
patients with WM. A principal and unique strength of this analysis is
that it is based on a large prospective data set with a uniform
follow-up. The prognostic variables (hemoglobin and Our data have several implications for the care of patients with WM.
Measurement of serum
We thank Jeana Cromer, Monica Yee, Patricia O'Kane, and Diana Lowry for invaluable assistance with data monitoring; Mike LeBlanc for discussions about statistical analysis; and all participating physicians and clinical research associates for their interest and participation in this study. This paper is dedicated to the memory of Dr Sidney Salmon, who led the myeloma committee at SWOG for the entire 10 years that it took to complete this study.
Submitted October 30, 2000; accepted March 5, 2001.
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, Department of Health and Human Services: CA38926, CA32102, CA20319, CA22433, CA46441, CA58416, CA37981, CA13650, CA66636, CA21115, CA13612, CA35261, CA12644, CA76462, CA35192, CA45450, CA04919, CA35090, CA58686, CA45807, CA42777, CA45377, CA46282, CA04920, CA58861, CA76447, CA67663, CA46113, CA45560, CA63850, CA14028, CA35431, CA35176, CA27057, CA76132, and CA12213.
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: Southwest Oncology Group (SWOG-9003), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217.
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Top
Abstract
Introduction
-interferon; anti-CD20
monoclonal antibody; and high-dose therapy.
Airlie House, Virginia, November 1997.
J Clin Oncol.
1999;17:3835-3849