Department of Pathophysiology, Medical School, National University of Athens, Greece.
Correspondence to: M. Voulgarelis, Department of Pathophysiology, Medical School, National University of Athens, M. Asias 75, Goudi, 11527 Athens, Greece. E-mail: mvoulgar{at}med.uoa.gr
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Methods. Four SS patients with aggressive marginal zone NHL were enrolled in this trial. All patients were classified according to the newly proposed revised EuropeanAmerican classification of lymphoid neoplasms. Three out of four patients also had mixed cryoglobulinaemia (MC) of type II. They were treated every 3 weeks for eight cycles of CHOP. Patients also received rituximab, at a dose of 375 mg per square metre, on day 1 of each of the eight cycles of CHOP. Four weeks after completion of the eighth course of CHOP plus rituximab and every 6 months thereafter, patients were re-evaluated for response.
Results. Complete remission of lymphoma was achieved in all four patients. The lymphoma patients remained in remission for a period of 23, 15, 12 and 10 months respectively, while certain signs and symptoms of MC type II (purpura, peripheral neuropathy and arthralgias) significantly improved with treatment. In addition, the titres of circulating cryoglobulins and RF decreased, while C4 levels returned to normal.
Conclusion. CHOP plus rituximab was well tolerated and proved effective in SS patients with aggressive NHL. Our observations may warrant a larger controlled trial to assess the effectiveness of this regimen in such patients.
KEY WORDS: Sjögren's syndrome, Lymphoma, Rituximab, Cryoglobulinaemia
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Pretreatment evaluation
All patients fulfilled the European American classification criteria of SS [7]. For each individual, a special Sjögren's record was completed and included the exocrine and systemic manifestations, haematological and biochemical studies, serum and urine protein electrophoresis and immunofixation, immunoglobulin quantitation, ß2-microglobulin, circulating cryoglobulins, serum levels of the complement components C3 and C4, ANA, autoantibodies to Ro/SSA and La/SSB, bone marrow biopsy, and computed tomography (CT) scans of the thorax and abdomen. Clinical examination of the oropharynx, gastroscopy and cerebrospinal fluid analysis were also included in staging procedures. All patients were staged by the Ann Arbor and International Prognostic Index scoring systems [8, 9]. Neurological assessment included strength evaluation, electromyography, motor and sensory nerve conduction velocity and sensory-evoked potential. Electromyography confirmed the diagnosis of chronic polyneuropathy in two of two patients tested at baseline, which was consistent with axonal plus myelin damage and detected a sensory and a mild motor involvement in both. Neuropathic symptoms (pain and paraesthesias) were also graded according to a patient-scored visual analogue scale (VAS) (range 010).
Response criteria for lymphoma patients
Tumour response was graded as (a) complete response (CR), (b) partial response, (c) no response or (d) progressive disease. CR was defined as complete disappearance of all measurable disease parameters for at least 4 weeks on physical examination and chest, abdomen and pelvis CT scans; B symptoms (fever, night sweats and weight loss), if present, had to be abated. Partial response was defined as a 50% reduction in the sum of the products of the cross-sectional diameters of all known lesions for at least 4 weeks. No response was defined as less than a partial response, while progressive disease was defined as an increase of 25% in measurable disease.
Treatment plan
Patients received the combination of 750 mg/m2 of cyclophosphamide on day 1; 50 mg/m2 of doxorubicin on day 1; 1.4 mg/m2 of vincristine, up to a maximal dose of 2 mg, on day 1; and 40 mg/m2 of prednisone per day for 5 days. They were treated every 3 weeks for eight cycles of CHOP. Patients also received rituximab, at a dose of 375 mg/m2, on day 1 of each of the eight cycles of CHOP. No radiation therapy was given or recommended at the end of treatment. All the patients received central nervous system prophylaxis, which consisted of an intrathecal infusion of 12.5 mg of methotrexate. Four weeks after the completion of the combined R-CHOP chemotherapy, staging was repeated for all patients to assess response. Treatment was withheld between two courses of chemotherapy until the neutrophil or platelet counts reached 1000 and 100 000/µl respectively. No reduction in dose was done in subsequent courses.
Follow-up
All patients were followed up monthly with blood cell counts and biochemistry profile during the entire treatment period of 24 weeks. Four weeks after completion of the eighth course of R-CHOP and every 6 months thereafter, the patients were re-evaluated for response (exocrine and non-exocrine manifestations, cryoglobulinaemia, autoantibody profile etc.) using the same diagnostic and imaging techniques as those used before treatment. A response in peripheral neuropathy was considered present if a decrease in VAS greater than 25% was noted. Electromyography was repeated whenever possible.
Toxicity
The standard criteria of the Eastern Cooperative Oncology Group were used for the evaluation of haematological and non-haematological toxicities [8]. Grade III and IV toxicities were considered significant.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
All four patients received the planned dose of chemotherapy, achieved CR after 8 cycles of R-CHOP therapy and remained in CR after 23, 15, 12 and 10 months. ß2-Microglobulin and lactate dehydrogenase (LDH) levels were also normalized. Monoclonal cryoglobulins, purpura and arthralgias disappeared after four courses of therapy in patients 1 and 4 and after five courses in patient 2. In all patients with MC type II, the RF titre decreased and a significant increase in the serum levels of C4 was observed; ANA titres and anti-Ro/La expression were unchanged (Table 3). An improvement in subjective symptoms of sensory peripheral neuropathy and a marked improvement in muscle strength were noticed in patients 2 and 4. In patient 4 the electromyography pattern was unchanged with respect to baseline 5 months after completion of therapy. Serum and urine monoclonal bands disappeared in patients 1 and 2.
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
In a multicentre European study, the majority of SS-associated NHLs were primarily low-grade, extranodal, marginal zone B-cell lymphomas of the MALT type. In this study, three out of 33 of the cases showed a high-grade transformation, which suggests that lymphomas in SS patients potentially evolve towards a less differentiated cell type in some patients [1]. Moreover high-grade transformation to diffuse large B-cell lymphomas has been seen in some MALT lymphomas, in which the clonal relation between the high- and low-grade component has been confirmed by molecular analysis [12]. SS-NHL patients with high or intermediate grade lymphoma treated with CHOP alone have a rather poor outcome, with an estimated median overall survival of 21 months [1]. Rituximab is used for the treatment of a wide variety of lymphomas, including diffuse large B cell lymphomas, but single-agent therapy with rituximab had only moderate activity in patients with advanced extranodal, marginal zone B-cell lymphomas [13]. These observations, together with data indicating that R-CHOP had a significant clinical effect in diffuse large B-cell lymphoma, increasing both response rate and survival compared with CHOP alone [4], prompted us to use this regimen in four SS patients with aggressive NHL. The major point of our study was that R-CHOP induced sustained CR in all SS patients with aggressive B-cell NHL for a follow-up period that ranged from 10 to 23 months (mean 15 months). Moreover, the extranodal manifestations of our patients, such as peripheral neuropathy and skin vasculitis, disappeared after eight cycles of R-CHOP. The remission of these symptoms and signs was accompanied by a decrease in the circulating mixed monoclonal cryoglobulins as well as an increase in C4 levels. Thus, R-CHOP appears to be effective in controlling both the autoimmune and the neoplastic process in these patients. In a recent study, patients with aggressive lymphomas receiving intensive conventional chemotherapy with the ACVBP regimen (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone) seemed to have better event-free and overall survival with this regimen compared with CHOP [14]. Therefore, the association of rituximab and ACVBP in SS patients with high-grade lymphomas should also be evaluated.
There is strong evidence that B-cell clones that are responsible for the myoepithelial sialadenitis in SS produce Ig with RF activity. Secreted by these proliferating RF-positive B-cell clones, type II mixed cryoglobulins are frequently detected in SS patients [15]. Rituximab efficiency in the type II, hepatitis C virus (HCV)-related cryoglobulinaemia has already been demonstrated [16]. The findings that rituximab was effective against RF-positive B-cell clones provided the trigger for using it for selective B-cell blockade in SS-related type II MC. The significant decrease in serum RF levels and cryoglobulins and the clinical improvement of purpura and peripheral neuropathy in our patients further support these data.
Previous studies suggested that rituximab selectively inhibits IgM-positive CD20+ plasma cells, which produce autoantibodies [17]. In our study, the titre of ANA and anti-Ro/La antibodies did not change; this observation indicates that the combination treatment with R-CHOP did not have any effect on antibody-producing B-cell clones, such as populations of long-lived plasma cells [18]. These cells, most likely sheltered in the splenic red pulp, bone marrow and inflamed tissues, secrete autoantibodies and therefore supply the antibody-mediated autoimmune memory in the absence of any detectable memory B cells [18]. The inability of R-CHOP to fully suppress autoimmune responses that are mediated by long-lived plasma cells gives further insight into the pathogenetic mechanisms governing B-cell expansion and autoantibody production.
In conclusion, we found that combination of R-CHOP was a well tolerated and efficient regimen for the treatment of the aggressive SS-associated lymphoma in our small group of patients. However, the effectiveness of this treatment should be further assessed by larger controlled, multicentre trials.
![]() |
Acknowledgments |
---|
The authors have declared no conflicts of interest.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|