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- Patients and methods
This study examined the outcome of 248 Waldenstrom macroglobulinaemia (WM) rituximab-naïve patients who responded to a rituximab-containing regimen. Eighty-six patients (35%) subsequently received maintenance rituximab (M-Rituximab). No differences in baseline characteristics, and post-induction categorical responses between cohorts were observed. The median rituximab infusions during induction was 6 for both cohorts; and 8 over a 2-year period for patients receiving M-Rituximab. Categorical responses improved in 16/162 (10%) of observed, and 36/86 (41·8%) of M-Rituximab patients respectively, following induction therapy (P < 0·0001). Both progression-free (56·3 vs. 28·6 months; P = 0·0001) and overall survival (Not reached versus 116 months; P = 0·0095) were longer in patients who received M-Rituximab. Improved progression-free survival was evident despite previous treatment status, induction with rituximab alone or in combination therapy (P ≤ 0·0001). Best serum IgM response was lower (P < 0·0001), and haematocrit higher (P = 0·001) for patients receiving M-Rituximab. Among patients receiving M-Rituximab, an increased number of infectious events were observed, but were mainly ≤grade 2 (P = 0·008). The findings of this observational study suggest improved clinical outcomes following M-Rituximab in WM patients who respond to induction with a rituximab-containing regimen. Prospective studies aimed at clarifying the role of M-Rituximab therapy in WM patients are needed to confirm these findings.
Rituximab is an active agent in the treatment of Waldenstrom macroglobulinaemia (WM), a CD20-expressing indolent B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy (Owen et al, 2003). With the use of single agent rituximab, overall response rates of 20–30% have been reported with a standard induction regimen of four weekly infusions, and progression-free survival (PFS) of 1 year (Foran et al, 2000; Treon et al, 2001; Gertz et al, 2004). With the use of an extended schedule of four weekly infusions, followed by four additional weekly infusions at week 12, response rates of 40–50% and PFS of 16–30 months have been reported (Dimopoulos et al, 2002; Treon et al, 2005). Because of the non-myelosuppressive nature of rituximab, and its potential to synergize with various anti-neoplastic agents including alkylators, nucleoside analogues, immunomodulatory drugs, and proteasome inhibitors, its investigation in combination regimens has been vigorously pursued (Treon et al, 2006; Dimopoulos et al, 2009). These studies have generally revealed higher overall response rates (70–90%) and PFS (3–4 years), and in some studies, improved categorical responses over monotherapy. Despite these successes, most patients with WM eventually show disease progression.
In an effort to improve outcome in WM patients, maintenance rituximab (M-Rituximab) has increasingly become used following reports of improved categorical responses, as well as PFS and/or overall survival (OS) in other indolent B-cell lymphomas (Hainsworth et al, 2002, 2009; Ghielmini et al, 2004; Forstpointner et al, 2006; van Oers et al, 2010). However, the efficacy and safety of M-Rituximab has not been investigated in WM patients. As such, we examined the outcome of 248 rituximab-naïve WM patients who responded to a rituximab-based induction therapy, and assessed the impact of M-Rituximab therapy on categorical response attainment, immunoglobulin levels and blood counts, PFS and OS, and safety.
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- Patients and methods
The paucity of published data on the use of M-Rituximab in WM patients prompted us to investigate the outcome of 248 rituximab-naïve patients who demonstrated a response to a rituximab-based therapy, and who subsequently were observed or who underwent M-Rituximab therapy. The strength of this study is the large population of WM patients included, as well as the long follow-up period available for these patients. In addition, both cohorts exhibited similar baseline and response characteristics following induction therapy, permitting an informative analysis. Despite these strengths, unforeseen biases, which could have influenced patients selected for observation versus M-Rituximab therapy, as well as patient follow-up need to be kept in mind when interpreting the outcomes of this retrospective analysis.
While the use of M-Rituximab has not been previously investigated in WM, two previous studies addressed the role of an extended schedule of rituximab administration, i.e. four weekly infusions followed by four more weekly infusions in WM (Dimopoulos et al, 2002; Treon et al, 2005). These single arm studies showed higher overall response rates and possibly time to progression in comparison to studies utilizing standard four weekly infusions. However, the impact of long term M-Rituximab in WM has remained to be clarified, largely because of the uncommon nature of the disease as well as priorities by investigators in identifying novel, WM-directed therapeutics.
As part of these efforts, we observed a fourfold improvement in categorical responses in patients receiving M-Rituximab versus those who were observed after induction therapy. The achievement of a better categorical response is associated with improved PFS in WM patients treated with a rituximab-containing regimen (Treon et al, 2011). However, attainment of CR has been <10% in the majority of WM-directed clinical trials, including most of those incorporating rituximab as induction therapy. It is noteworthy that the CR rate in this study was significantly higher among patients who received M-Rituximab (16·3%), versus those who underwent observation (7·4%; P = 0·05), a finding that may have contributed to the improvements observed in PFS and OS in this study. Consistent with these findings, patients who underwent M-Rituximab also exhibited significantly better serum IgM responses, as well as improvements in their haematocrit versus those patients who underwent observation. These findings and the application of M-Rituximab may be particularly relevant from a clinical benefit point of view for WM patients presenting with morbidity related to serum IgM, i.e. IgM-related neuropathy, cryoglobulinaemia, cold agglutinaemia, and other autoimmune processes, hyperviscosity related to elevations in serum IgM levels, as well as patients presenting with symptomatic anaemia (Treon, 2009).
The important recognition in this study were the significant improvements noted in both PFS and OS in WM patients who received M-Rituximab. Among all patients who received M-Rituximab, PFS was nearly double that of patients who underwent M-Rituximab therapy (56 vs. 28 months). Improved PFS was evident despite previous treatment status, induction with rituximab alone or in combination therapy (P ≤ 0·0001). OS, defined as death from any cause, was also significantly longer in patients who received M-Rituximab. These observations are consistent with those made in studies addressing the role of M-Rituximab in other indolent B-cell lymphomas (Hainsworth et al, 2002, 2009; Ghielmini et al, 2004; Forstpointner et al, 2006; van Oers et al, 2010).
Consistent with the reporting of other studies addressing the role of M-Rituximab in other indolent B-cell lymphomas, we did not encounter any unexpected toxicities with M-Rituximab in WM patients (Hainsworth et al, 2002, 2003, 2009; Ghielmini et al, 2004; Forstpointner et al, 2006; Wenger et al, 2008; Taverna et al, 2009; van Oers et al, 2010). A higher incidence of respiratory tract infections was observed among patients receiving M-Rituximab, though nearly all of these infections were grade 2 or less. In addition, there was no difference in the incidence of hospitalizations over the follow-up period between both cohorts. Respiratory tract infections, particularly bronchitis and sinusitis, are common in WM patients, and have been speculated to be on the basis of IgA and IgG hypogammaglobulinemia, a frequent finding in WM (Treon, 2009; Hunter et al, 2010). A recent study found no correlation between serum IgA and IgG levels and recurring infections in WM patients, and recommended against routine intravenous immunoglobulin (IVIG) replacement (Hunter et al, 2010). The use of IVIG replacement should however be considered for those WM patients who demonstrate particularly severe recurring sinus and bronchial infections (Treon, 2009). In patients receiving M-Rituximab, and for whom IVIG replacement is being considered, spacing out of these agents should be considered given their potential to compete for similar sets of Fcγ receptors on immune effector cells.
Despite the above findings, many questions remain about the use of M-Rituximab in WM patients. As with other indolent B-cell lymphomas, the ideal schedule and duration of M-Rituximab therapy remains to be determined. Also, these studies did not address the benefit of M-Rituximab over re-treatment upon progression, which is currently being addressed in a prospective study by the Eastern Cooperative Oncology Group, utilizing rituximab in other indolent B-cell lymphomas (Kahl et al, 2007).
In summary, the findings of this observational study suggest improved clinical outcomes following M-Rituximab in WM patients who respond to induction with a rituximab-containing regimen. Prospective studies aimed at clarifying the role, ideal administrative schedule and duration for M-Rituximab therapy in WM patients are needed to confirm these findings.