Annals of Oncology Advance Access published online on October 3, 2008
Annals of Oncology, doi:10.1093/annonc/mdn636
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Rituximab monotherapy for primary cutaneous B-cell lymphoma: response and follow-up in 16 patients
1 Department of Dermatology, Medical University of Vienna
2 Department of Dermatology, Rudolfstiftung Hospital, Vienna
3 Karl-Landsteiner-Institute for Dermatological Research, Landesklinikum St Pölten, St Pölten
4 Department of Pathology, Wilhelminen Hospital
5 Department of Clinical Pathology, Medical University of Vienna
6 Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Austria
* Correspondence to: Dr M. Raderer, Division of Oncology, Department of Internal Medicine I, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Wien, Austria. Tel/Fax: +43-1-40400-2296; E-mail: markus.raderer{at}meduniwien.ac.at
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Abstract |
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Background: We have carried out a retrospective analysis to evaluate the therapeutic value of the anti-CD20 antibody rituximab in 16 consecutive patients with primary cutaneous CD20+ B-cell lymphomas.
Patients and methods: Sixteen patients (4 females, 12 males) with a median age of 54 years received systemic therapy with rituximab 375 mg/m2 once weekly for four or six consecutive weeks. Eleven patients had primary cutaneous follicle center cell lymphoma and five patients had a primary cutaneous marginal zone B-cell lymphoma.
Results: Of the 16 patients with PCBCL, 14 patients (87.5%) achieved complete remission (CR). In two patients, partial remission was obtained and additional focal radiotherapy was applied, which resulted in final CR. Five to 14 (35%) patients with CR relapsed, in an interval between 6 and 37 months. There were no severe side-effects.
Conclusions: On the basis of our results, single-agent treatment with i.v. rituximab appears to be feasible and safe and results in a high rate of durable remissions. Judging from our data, it appears to be an attractive treatment option and should be directly compared with local radiotherapy.
cutaneous B-cell lymphoma, rituximab, systemic treatment
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introduction |
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Primary cutaneous B-cell lymphomas (PCBCLs) account for
25% of all cutaneous lymphomas [1, 2]. While ample data on the clinicopathological profile, the course and the treatment of primary cutaneous T-cell lymphomas have been generated, an understanding of PCBCL remains somewhat more elusive. In fact, representative studies of patients with PCBCL are scarce due to the rarity of the disease. In addition, interpretation of data is further hampered by the fact that cutaneous presentation of B-cell lymphoma has historically not always been distinguished between primary and secondary cutaneous involvement from nodal disease [3, 4].
According to the World Health Organization (WHO)–European Organisation for Research and Treatment of Cancer (EORTC) classification [2], three major groups of PCBCL are distinguished: follicle center cell lymphomas (FCL) and marginal zone B-cell lymphomas (MZL), both representing 75% of cases and primary cutaneous diffuse large B-cell lymphoma, leg type (DLBCL). Both FCL and MZL usually have an indolent clinical course with the estimated disease-specific 5-year survival exceeding 95% [2, 5]. Although the clinical course is generally favorable, recurrence rates following initial treatment are high and vary between 25% and 68% [5]. The characteristic clinical presentation consists of erythematous to violaceous plaques, nodules or tumors frequently surrounded by papules and plaques [6, 7]. Skin lesions usually have a regional distribution, preferentially occurring on the head (26.4%) and the trunk (49.8%) [5, 6]. In view of the clinical presentation, i.e. the multifocal appearance together with the indolent course of the disease, choice of treatment has to be carefully considered. Currently, local treatment modalities including surgery and local radiotherapy are most widely applied [5, 8, 9] but bear the risk of relapse and/or esthetic impairment. In the absence of controlled trials, there is still no clear consensus about the treatment modality of choice in PCBCL. Rituximab, a human–mouse chimeric mAb that targets the CD20 antigen, is successfully being used in the treatment of nodal B-cell non-Hodgkin’s lymphomas, either alone or mostly in combination with chemotherapy [10]. Recently, rituximab has also been given consideration for treatment for CD20+ PCBCL either systemically or applied intralesionally, albeit in small patient collectives and case reports [11–17]. Given the scarce data available on the use of rituximab in PCBCL, we have carried out a retrospective analysis of patients with cutaneus B-cell lymphomas treated with systemic rituximab monotherapy at our institution.
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patients and methods |
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An evaluation of patients with PCBCL treated at our institution from January 2003 to December 2007 identified 16 patients (4 females, 12 males) with a median age of 54 years (range 25–73) undergoing therapy with rituximab for PCBCL. Patient data are compiled in Table 1. Eleven patients had primary cutaneous FCL and five patients had MZL, as classified according to the WHO–EORTC classification. Immunohistochemistry and molecular cytogenetics were done as described in detail elsewhere [18].
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Before treatment, extensive staging was carried out including physical examination, laboratory screening, skin inspection, computed tomography of the thorax and abdomen, bone marrow biopsy and sonography of all lymph nodes. None of the patients had extracutaneous involvement, apart from patient 7 (Table 1), in whom FCL had directly spread from a cutaneous nodule to the bone of the occipital skull forming an epidural mass of 1.2 x 1.2 cm. All patients received i.v. therapy with rituximab 375 mg/m2 once weekly for four consecutive weeks. In patients showing complete disappearance of cutaneous lesions after four infusions, therapy was discontinued. In patients developing only partial response, i.e. showing residual lesions, two further infusions were given. None of the patients received more than six infusions. During treatment with rituximab, no other cancer-specific treatments were given in our patients. Before therapy, blood tests were carried out including complete blood counts with differential and chemistry and i.v. diphenhydramine 60 mg and oral paracetamol 1000 mg was given on a routine basis before each infusion of rituximab. Cutaneous involvement was clinically evaluated weekly before therapy. Follow-up visits after the last treatment cycle included physical examination, laboratory screening and skin inspection every 8 weeks for 6 months, then at 3- to 6-monthly intervals.
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results |
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According to the WHO–EORTC classification, the cutaneous lesions of 11 patients were diagnosed as FCL and as MZL in five patients. Immunophenotypically, the 11 FCLs were CD20+, bcl-6+; CD10 was expressed in six and bcl-2 in two of these patients. Cytogenetic findings are described in Table 2.
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A total of 16 consecutive patients were included in our analysis. Eleven patients had been pretreated with either surgery or local radiotherapy and received rituximab at first relapse, five patients had not been pretreated and were given rituximab as first-line therapy (patients 10–14, Table 1). In the four patients pretreated with radiation, the following doses had been administered: 24, 31 and 40 Gy in two patients.
The time between initial therapy and relapse leading to therapy with rituximab was 2–34 months in the pretreated patients. Patient characteristics, response rates and recurrences following rituximab treatment are specified in Table 1. Four patients had a single nodule on the head, while 12 patients showed multifocal disease with numerous lesions on the head, trunk, right arm and right leg. The four patients with unilocular disease on the head all had refused radiotherapy due to the potential durable hair loss caused by irradiation of the cranium. All patients responded to therapy and complete clinical remission (CR) was obtained in 14 of 16 patients (87, 5%), and due to disappearance of all lesions, no ‘blind’ biopsies in formerly involved sites were carried out. In the two remaining patients, additional local radiotherapy was required to achieve CR. In one patient with FCL (patient 7, Table 1), cutaneous–subcutaneous nodules on the skull had disappeared after four infusions, but a control magnetic resonance imaging (MRI) of the epidural mass showed no reduction in size. In spite of further two infusions of rituximab, the epidural lesion increased to 1.4 x 1.4 cm according to an MRI carried out 8 weeks later. In view of this, radiotherapy was applied to this lesion, which resulted in ongoing CR. The other patient (patient 15, Table 1) had an MZL with numerous lesions on the back and though a total of six cycles was administered, CR could only be achieved after local radiotherapy on the remaining lesions. No cytogenetic abnormalities were detected in this patient. Ten patients had CR after four infusions of rituximab, while five patients required six infusions for CR and one patient received only one infusion. Disease recurrence occurred in 3 of 11 patients with FCL (27%) after 6, 18 and 37 months and in two of five (40%) patients with MZL after 7 and 11 months (see Table 1). Of the five patients with MZL, two patients experienced recurrent disease and one patient partial remission (PR) (Table 1). In one patient (patient 13, Table 1) recurrences were frequent and remissions short lived. In this patient (Table 2), cytogenetic analysis revealed the karyotype 46,XY[7]/46,XY,dup(1)(q21q42),del(6)(q23),dup(13)(q22q34),t(14;18)(q32q21)[8] by G banding, and a subsequent FISH study disclosed that the immunoglobulin heavy-chain locus (IGH) and the MALT1 gene were rearranged by this translocation.
Treatment was well tolerated in most patients and only two patients (patients 7 and 9, Table 1) experienced moderate rituximab-associated side-effects consisting of flush in one case. In patient 9, rituximab was stopped after a total dose of 500 mg due to flush and the sensation of heat at the patients’ request. Following this incident, the patient refused any further therapy. Nevertheless, a control visit 4 weeks after interruption of therapy showed complete disappearance of the lymphoma, thus the patient was rated as CR.
Taken together, 5 of 16 patients have relapsed between 6 and 37 months after CR (for progression-free survival see also Figure 1). All patients could be salvaged with alternative approaches resulting in a second CR; for detailed information, see Table 1. Of interest is the fact that four patients were retreated with rituximab, resulting in CR in one patient and PR in further three cases, which could be converted to CR with radiation or excision (see Table 1).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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While having predominantly been treated locally in the past, recent years have seen scattered reports of the application of either systemic or intralesional rituximab in patients with PCBCL [11–17]. Due to the relative rarity of PCBL, some reports included various histological subtypes of PCBCL with highly variable clinical courses [15, 16]. Especially DLBCL is associated with a poor prognosis with an overall 5-year disease-specific survival rate of 41%. In this disease, combining rituximab with chemotherapeutic agents seems to improve outcome [19], as has also been demonstrated in a wide spectrum of nodal lymphoma types. For the ‘indolent’ subtypes of PCBCL including FCL and MZL, optimal management is less clear and therapeutic decisions vary individually. While a watch-and-wait policy might initially be adopted in some patients, localization of the lesions may warrant therapy due to esthetic impairment and the patient's consecutive wish for therapy even in the absence of an aggressive clinical course. The clinical presentation with a high percentage of multilocular lesions, the high recurrence rates and the potential for local recurrences within the same anatomic site indicate the requirement for a potent long-acting therapy devoid of toxic side-effects.
Apart from numerous case reports with successful systemic rituximab therapy [11, 13], the series reported by Gellrich et al. [15] shows the highest number of patients treated successfully with systemic single-agent rituximab. In this series, the majority of patients had indolent types of PCBCL, and only one patient suffered from DLBCL in this collective. Two-thirds of the patients disclosed single nodules that would have been potentially amenable to surgery or radiation, and all were treated with eight cycles of rituximab. The clinical overall response rate was high at 90%, and the authors concluded that their prolonged regimen contributed positively to the response rates and the favorable time to recurrence.
As opposed to this, a complete clinical remission could be obtained in 14 of 16 of our patients, with 11 patients receiving only up to four cycles and five patients six cycles, with 80% of them showing multilocular disease. Two patients (Table 1), however, had to undergo additional radiotherapy to persistent lymphoma foci to achieve complete remission (CR). In one patient, direct intracranial spread of the FCL was not affected by rituximab in spite of the fact that the multiple nodules and papules on the parietal and occipital area on the skull completely resolved after four cycles. The other patient showed a multilocular MZL that showed residual lesions after six cycles and therefore he received local radiotherapy together with two more infusions of rituximab.
While our results might indicate that response and time to recurrence do not necessarily need a prolonged course of rituximab treatment, as with a maximum of four cycles, CR could be obtained in 10 of 16 patients (62%), the series is too small to allow for extrapolation of the optimal duration of therapy and this aspect warrants further evaluation in the future. In fact, the aspect of prolonged treatment has also been recognized in nodal follicular lymphoma, where the relatively high rate of relapses has led to various trials on maintenance therapy with rituximab. In these studies, a beneficial effect of maintenance with rituximab has almost unequivocally been established. In view of these data from nodal follicular lymphoma, it might be tempting to speculate that prolonged treatment with rituximab might also be an attractive approach in cutaneous B-cell lymphomas in order to delay potential relapses. Interestingly, in patient 9 (Table 1) who presented with the smallest nodule, only 500 mg of rituximab was sufficient to obtain CR. After a median follow-up time of 37 months, all patients are alive and in CR. Apart from the high clinical efficacy, rituximab was generally well tolerated apart from the above-mentioned side-effects, which were mild and easily manageable. These data suggest that single-agent rituximab appears to be a reasonable treatment option in patients with FCL and MZL, especially in individuals with multilocular disease. Our data along with data from the literature, however, suggest a high efficacy also in patients with localized disease. While not constituting a direct comparison, our results appear to highly promising, as median times to recurrence of 10 months [20] have been reported with application of radiotherapy in patients with multilocular CBCL. It is especially tempting to perform a direct comparison with radiotherapy, as certain areas such as the capillitium are highly prone to radiation-induced long-term side-effect such as permanent hair loss.
In conclusion, in a subset of patients with multifocal or relapsed disease, or in patients with single lesions in distinct anatomic sites, systemic monotherapy with four infusions of rituximab seems to achieve good response rates with long CRs. The data, however, have to be interpreted with caution, as the number of patients is small and the median follow-up period is short at 37 months. In view of this, further studies on rituximab versus radiation are warranted in order to fully assess the value of anti-CD20 treatment in PCBCL. In addition, also combination of rituximab with chemotherapy or radioimmunotherapy targeting CD20 should be explored in the future, as this latter approach has been demonstrated to be safe and effective even in elderly patients with nodal follicular lymphoma.
Received for publication July 16, 2008. Revision received August 14, 2008. Accepted for publication August 18, 2008.
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