Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece
Received 15 November 2002; revised 7 January 2003; accepted 14 March 2003
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Abstract |
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Waldenstroms macroglobulinemia (WM) is an unusual lymphoplasmacytoid lymphoma characterized by the presence of a serum monoclonal immunoglobulin M. Although several studies have evaluated possible prognostic factors of this disease, few have focused on the survival and prognosis of symptomatic patients after the initiation of treatment.
Patients and methods:
Our study included 122 previously untreated patients with a median age of 67 years who required systemic treatment. Multiple variables were analyzed for their prognostic value on survival after initiation of treatment using univariate and Cox regression multivariate analysis.
Results:
The median overall survival was 106 months. Pretreatment factors associated with shorter survival were age 65 years, splenomegaly, B-symptoms (weight loss, fever or night sweats), hemoglobin <10 g/dl, platelets <100 x 106/dl, albumin <3.5 g/dl and bone marrow lymphoplasmacytic infiltrate
50%. In the multivariate analysis, the two variables with independent prognostic value were age
65 years and hemoglobin <10 g/dl. Furthermore, we were able to divide our patients into three risk groups based on the presence of two, one or none of these two adverse prognostic factors. The median survival times in the high-, intermediate- and low-risk groups were 46 months, 107 months and 172 months, respectively (P <0.0001).
Discussion
Our findings suggest that advanced age and anemia appear to be the two dominant prognostic factors for survival after initiation of treatment in patients with WM. These two readily available parameters can stratify the patients into three distinct subgroups and may help the selection of appropriate treatment.
Key words: prognosis, survival, treatment, Waldenstroms macroglobulinemia
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Introduction |
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WM is an infrequent disease that affects 1500 Americans each year; it is
1020% as common as multiple myeloma. Most patients with WM present with symptoms, signs or other complications that require prompt initiation of systemic treatment in order to reduce the proliferation of the malignant clone. However, several patients are diagnosed by chance and do not have symptoms, anemia, significant hepatosplenomegaly or lymphadenopathy, or complications associated with the presence of monoclonal IgM. Such asymptomatic patients are followed without any treatment for several months or years until there is evidence of disease progression [3].
WM is a relatively indolent disease with a median survival of 510 years in different series. Several studies have evaluated clinical and laboratory parameters associated with shorter or longer survival of patients with WM [411]. Most of these studies have included a mixed population of patients consisting of symptomatic patients who received treatment at diagnosis and of asymptomatic patients who required treatment several months or years after diagnosis. Thus, in several studies it was not clear which variables were predictive specifically for the symptomatic patients who needed treatment. We thus designed a retrospective study that included previously untreated patients who required systemic treatment, and we focused on their survival and prognosis after the initiation of treatment.
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Patients and methods |
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A database was constructed, which included the following parameters: age, gender, presence of B-symptoms, splenomegaly, lymphadenopathy, hyperviscosity, cryoglobulinemia, cold agglutinin anemia, amyloidosis, neuropathy, hypercalcemia, bone lesions, or other extranodal involvement. Other parameters included complete blood counts, liver and renal function tests, serum monoclonal protein, serum albumin, quantitation of serum immunoglobulins, serum ß2-microglobulin, type of light chain, Bence Jones proteinuria, serum LDH, and percentage and pattern of bone marrow infiltration. Moreover, the primary indication of the need to start treatment, the type of primary treatment and the response to treatment were coded.
Complete response was defined as the disappearance of the monoclonal protein by immunofixation, resolution of lymphadenopathy and organomegaly, and <20% normal appearing lymphocytes in the bone marrow. Partial response was defined as 50% reduction of serum monoclonal protein concentration for at least 2 months along with
50% reduction of tumor infiltrate at all involved sites. The disease was considered stable when the reduction of serum monoclonal protein ranged from 0% to <50% without an increase in lymphadenopathy and organomegaly, and without evidence of additional disease complications. Patients were rated as having progressive disease when they did not meet the criteria for response or stable disease.
Survival was considered from the first day of treatment to the time of death or last follow-up. Several clinical and laboratory characteristics were considered for analysis concerning their individual and simultaneous effects on survival. These parameters were adapted from previous series that evaluated prognostic factors in Waldenstroms macroglobulinemia and included: age, gender, hyperviscosity, B-symptoms (weight loss, fever or night sweats), splenomegaly, lyphadenopathy, levels of monoclonal protein, type of light chain, anemia, thrombocytopenia, leukopenia, hypoalbuminemia and bone marrow infiltration. Survival curves were plotted using the KaplanMeier method [12]. Statistical comparisons between actuarial survival curves were based on log-rank and Wilcoxon tests [13, 14]. The cut-off point of each variable was selected by comparison of the alternative cut-off points based on the minimum P-value method [15]. Variables considered for possible inclusion in the Cox analysis were those for which there was a significant association in univariate analysis (P <0.05) or for which previous studies had suggested a possible association [16]. The stepwise regression procedure was stopped when the P value for entering an additional factor was >0.01. The model was tested both by expressing values in a continuous way (continuous variables) and by grouping them into categories (dichotomous variables). Since ß2-microglobulin was recorded in 62 patients only, it was not included in the Cox model.
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Results |
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Primary reason to start treatment and response to treatment
The most common reason to indicate the need for treatment initiation was anemia (Table 2). Symptomatic hyperviscosity necessitated treatment in one-fifth of patients. Significant or increasing lymphadenopathy and/or splenomegaly or the presence of B-symptoms were the primary cause for treatment in several patients. Ninety-five patients (78%) were treated with alkylating agents. Chlorambucil with or without prednisone was the primary treatment in 60% of patients. Some patients received primary treatment that included combinations of alkylating agents with a vinca alkaloid such as cyclophosphamide, vincristine and prednisone (CVP) (nine patients), or with a nitrosurea such as vincristine, cyclophosphamide, melphalan, carmustine and prednisone (VMCBP) (five patients). Eight patients were treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Only nine patients were treated up front with fludarabine and 19 patients received miscellaneous treatments, including rituximab in 12 patients. Overall, an objective response (complete or partial response) was documented in 58% of patients. Complete responses were rare and were seen in only five patients. There was no difference in the response rate and survival among the different regimens.
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Multiple parameters were analysed for their possible prognostic impact on patient survival. The univariate analysis showed that the following factors were associated with an impaired survival: age 65 years, symptomatic disease, splenomegaly, hemoglobin <10 g/dl, platelets <100 x 106/dl, albumin <3.5 g/dl and bone marrow lymphocytes
50% (Table 3). Other parameters that were not associated with survival included: gender, type of light chain, WBC <4 x 106/dl, levels of monoclonal protein, hyperviscosity and lymphadenopathy. In the multivariate analysis, the two variables with independent prognostic value were the age
65 years and hemoglobin <10 g/dl (Table 4). Subsequently we divided our patients into three risk groups based on the presence of two, one or none of the adverse prognostic factors. As shown in Table 5, we were able to separate our patient population into three distinct risk groups with very different survival times. Approximately one-quarter of our patients were assigned to a low-risk group with a median survival of 14 years, whereas one-quarter of them, who had both adverse disease features, survived for a median of 4 years (Figure 1).
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Discussion |
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We restricted our analysis to those patients requiring treatment in order to obtain a more homogeneous patient population. Indeed, most studies reported so far have also included asymptomatic patients who were followed for several months or years without treatment, and have analyzed and compared the outcome of asymptomatic patients with that of patients requiring treatment soon after diagnosis. Among those asymptomatic patients, some individuals with IgM monoclonal gammopathy of undetermined significance might also have been included.
All published series with evaluated prognostic factors for survival in WM are listed in Table 7. In some series, up to 30% of those patients included were asymptomatic. In all but two studies a Cox regression multivariate analysis was performed. A review of these studies indicates that in most series, advanced age and anemia are the dominant adverse prognostic factors. Our data confirmed those observations. Our univariate analysis indicated that age 65 years, B-symptoms, splenomegaly, hemoglobin <10 g/dl, platelet count <100 x 106/dl, albumin <3.5 g/dl and bone marrow lymphocytosis
50% were adverse prognostic factors. However, the stepwise regression analysis showed that the two independent variables were advanced age and anemia. By combining these two adverse prognostic factors we were able to stratify our patients into three risk groups (high, intermediate and low risk), with significantly different median survival times of 4, 9 and 14 years, respectively.
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Two recently published studies of prognostic factors in WM that applied a multivariate analysis have indicated that serum ß2-microglobulin is a significant adverse prognostic factor. Dhodapkar et al. [11] found that elevated serum ß2-microglobulin levels, anemia and low levels of serum monoclonal protein were significant adverse prognostic factors for survival. Garcia-Sanz et al. [8] indicated that high ß2-microglobulin and hyperviscosity were the most significant variables. Baseline levels of serum ß2-microglobulin were available in a fraction of our patient population who were recently diagnosed and in whom few events have occurred. Thus, we were not able to evaluate fully the role of this variable in our patient population. Nevertheless it appears that the 3-year survival of patients with lower levels of ß2-microglobulin is better than that of patients with higher levels. The dominant prognostic value of serum ß2-microglobulin in WM is in accordance with its role in multiple myeloma and chronic lymphocytic leukemia [18, 19]. Although serum ß2-microglobulin is considered a reflection of tumor mass, we observed that there was a significantly positive correlation between age and serum ß2-microglobulin levels. Thus, the prognostic significance of serum ß2-microglobulin may be partially explained by this finding.
We conclude that advanced age and anemia appear to be the two dominant prognostic factors for survival after the initiation of treatment in patients with WM. When baseline serum ß2-microglobulin levels are unavailable, these two readily available variables can stratify the patients into three distinct subgroups, and may help the selection of appropriate treatment and the evaluation of the effect of treatment.
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Footnotes |
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