Phase II Study of Oxaliplatin for Treatment of Patients With Mucosa-Associated Lymphoid Tissue Lymphoma
http://www.100md.com
《临床肿瘤学》
the Department of Medicine I, Division of Oncology and Hematology, Department of Radiology, and Department of Pathology, University of Vienna
Center of Excellence in Clinical and Experimental Oncology, Vienna, Austria.
ABSTRACT
PURPOSE: Various chemotherapeutic regimens have been applied for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, but no standard regimen has been identified to date. In view of the activity of oxaliplatin (L-OHP) in various types of lymphoma, we performed a phase II study to evaluate the activity of L-OHP for treatment of MALT lymphoma. The primary objective of this study was to determine the objective response rate according to WHO standard criteria.
PATIENTS AND METHODS: A total of 16 patients with MALT lymphoma of various sites of origin (four of the ocular adnexa, five of the salivary glands, three of the stomach, two of the lung, and one of the colon and the breast) were administered L-OHP at a dose of 130 mg/m2 infused during 2 hours every 3 weeks. Restaging was performed every two cycles; treatment was continued until complete remission (CR) or for a maximum of six cycles in responders.
RESULTS: Sixty-five cycles were administered (median, four; range, two to six); toxicity consisted of transient sensory neuropathy in eight patients and nausea/emesis WHO grade 2 in two patients, whereas hematologic adverse effects (thrombocytopenia and leukocytopenia grade 2) occurred in only one patient each. Fifteen patients responded to chemotherapy, with nine achieving CR (56%), six (37.5%) achieving partial response, and one achieving stable disease; the median time to response was 4 months (range; 2 to 4 months).
CONCLUSION: These data suggest L-OHP is a highly active agent for treatment of MALT lymphoma. However, a longer follow-up is needed to judge whether these remissions are durable.
INTRODUCTION
Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) was initially defined by Isaacson and Wright,[1] and has been incorporated as a distinct entity into the recent WHO classification.[2] The large majority of occurrences are diagnosed in the stomach, but MALT lymphoma may arise in virtually any organ of the human body.[2] Because MALT lymphoma was thought to be a strictly localized disease, local treatment approaches, including surgery and radiation predominantly, were applied in the past. However, the finding of intraorgan[3] and systemic dissemination in a large percentage of patients,[4] as well as high relapse rates despite excellent local control with radiotherapy,[5] have resulted in attempts to evaluate systemic approaches.
At present, there is no chemotherapeutic standard treatment for patients with MALT lymphoma either presenting with disseminated disease or with relapsing/refractory disease after local treatment or after eradication of Helicobacter pylori (HP). Various chemotherapies have been tested, including alkylating agents such as cyclophosphamide or chlorambucil,[6] the nucleoside analogs cladridine[7] (2CdA) or fludarabine, the latter in combination with mitoxantrone,[8] as have combination regimens including cyclophosphamide, vincristine, and prednisone,[8] or mitoxantrone, chlorambucil, and prednisone.[9] In addition, two studies with the CD20 antibody rituximab have been reported in the literature.[10,11] However, only limited data obtained in prospective trials of chemotherapy exist. Thus, studies to evaluate the potential of new chemotherapeutic approaches in patients with advanced MALT lymphoma are justified.
Oxaliplatin (L-OHP) is a new platinum derivative of the diaminocyclohexamine family.[12] In terms of adverse effects as well as cytotoxic activity, it is substantially different from both cisplatin and carboplatin. In vitro data initially have identified it as active in a variety of solid tumors including GI cancers, and it has become part of standard therapy for advanced colorectal carcinoma.
Given that platinum compounds are applied in the treatment of various types of malignant lymphomas, L-OHP has also been investigated for treatment of patients with lymphoma. In a single-center study, Germann et al[13] found L-OHP to be active in patients with relapsed/refractory lymphomas of various histologies, resulting in an objective response rate of 40% when administered as single-agent therapy. When incorporated into a regimen of dexamethasone, high-dose cytarabine, and oxaliplatin, a response rate of 73% (53% complete remission [CR] and 20% partial remission [PR]) was found in 15 patients with lymphomas initially refractory or relapsing after therapy who were treated in a French study.[14] Comparable results were obtained by a British study group[15] using dexamethasone, high-dose cytarabine, and oxaliplatin in 24 patients with various types of lymphoma who experienced treatment failure to prior cytotoxic chemotherapy (response rate, 50%).
Because Germann et al[13] have included two patients with pretreated MALT lymphoma who achieved a PR after L-OHP treatment[12] and because of the excellent tolerance of the agent, we performed a prospective phase II study to investigate the activity of L-OHP in a larger cohort of patients with MALT lymphoma.
PATIENTS AND METHODS
Patients with histologically verified extranodal marginal zone B-cell lymphoma of MALT according to the WHO definition[2] without signs of transformation to diffuse large B-cell lymphoma were enrolled onto this prospective phase II study.
Patients with newly diagnosed MALT lymphoma or those experiencing relapse or progression after prior therapy were eligible. An interval of at least 8 weeks between completion of prior chemotherapy or radiation and initiation of treatment with L-OHP was required. For gastric lymphoma, patients with disease dissemination beyond the stomach were eligible immediately, whereas patients undergoing eradication of HP as initial therapy had to be refractory to antibiotic treatment for inclusion in the study. In such patients, progression of the disease or persistence of lymphoma without signs of regression for a minimum time span of 12 months after successful eradication of HP had to be present for study inclusion. Only patients aged older than 18 years with a WHO performance status 2 were eligible for study entry, and adequate renal (serum creatinine < 1.5 mg/dL), liver (total bilirubin < 2.0 mg/dL and AST level < 2x the upper limit of normal), and bone marrow (leukocyte count > 3,500/μL, platelet count > 100,000/μL) functions were also prerequisites for study entry. Patients with severe concomitant diseases, including a history of another malignancy, florid infections, psychiatric disorders, or peripheral neuropathies were not eligible. In female patients of childbearing age, a pregnancy had to be excluded before inclusion in the trial, and patients were required to use adequate contraception during the entire duration of treatment.
All patients gave written informed consent according to institutional guidelines before study entry, and application of L-OHP to patients with MALT lymphoma was approved by the local ethical committee.
All patients underwent extensive staging before initiation of therapy, consisting of ophthalmologic examination, otorhinolaryngologic investigation including sonography of the salivary glands or magnetic resonance imaging, if indicated, gastroscopy with multiple biopsies, endosonography of the upper GI tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen, and bone marrow biopsy. Staging was performed according to the Ann Arbor staging system as modified by Radaskiewicz et al[16] for gastric lymphoma. This system was applied because recently published series on extranodal lymphomas have adhered to this concept, and it enables staging of both gastrointestinal as well as extra-GI MALT lymphomas.
In all patients, routine assessment of MALT lymphoma–associated genetic aberrations was performed on biopsy samples. The presence of t(11;18)(q21;q21) was evaluated by reverse transcriptase polymerase chain reaction, whereas t(14;18)(q32;q21) involving IGH/MALT1, t(1;14)(p22;q32), and trisomies 3 and 18 were assessed by fluorescent in situ hybridization, as published previously.[17]
L-OHP was administered by intravenous infusion during 2 hours, repeated every 21 days. Routine premedication consisted of 8 mg intravenous dexamethasone along with an intravenous 5-hydroxytryptamine-3 antagonist administered immediately before application of chemotherapy. L-OHP (Eloxatin) was provided free of charge by Sanofi Synthelabo, Vienna, Austria.
CBCs were evaluated immediately at the start of each cycle and 2 weeks later. For a persisting nadir of the WBCs 3.0 x109/L (or neutrophiles < = 1.0 x109/L) and/or platelets 100 x109/L, the next treatment cycle was delayed 1 week until normal values were achieved. Restaging including computed tomography scan of thorax and abdomen, endosonography, and gastroscopy with histologic reassessment for gastric lymphoma and additional radiologic methods such as magnetic resonance imaging of the salivary glands for parotid lymphoma was performed every two cycles, and treatment was continued in the absence of progressive disease for a maximum of six cycles. For CR after the first reassessment, therapy was continued for and additional two courses up to a total of four. Assessment of response was performed according to standard guidelines,[18] and the times to relapse and failure-free interval were calculated from the first time of documented remission; follow-up time was calculated from the first application of oxaliplatin. For lymphoma restricted to the stomach/GI tract, histologic assessment of biopsy specimens served as the ultimate gold standard.
The primary end point of the study was the objective response rate induced by treatment with L-OHP in patients with MALT lymphoma (ie, rate of PRs and CRs according to Cheson et al,[18] whereas tolerance of chemotherapy in this cohort of patients was the secondary end point.) On the basis of the hypothesis of an expected response rate between 40% and 60%, the planned number of patients for inclusion in the study was 16 according to the Simon rule.[19]
RESULTS
A total of 16 consecutive patients with histologically verified MALT lymphoma according to the recent WHO classification[2] were eligible for inclusion and were enrolled onto the study. Nine patients were female and seven were male, and the median age was 66 years (range, 35 to 74 years). Five patients had lymphoma originating in the salivary glands, four in the ocular adnexa, three in the stomach, two in the lung, and one patient each had MALT lymphoma of the breast and the colon (patient characteristics are listed in [Table 1]). Nine of our 16 patients had Sj?gren's syndrome with respective clinical symptoms and serologic changes. No influence of treatment with L-OHP on the autoimmune disease was seen in our patients, neither in terms of clinical symptoms nor in terms of serologic changes; levels of rheumatoid factor, complement factor C4, and antinuclear antibody titer remained unchanged, and no influence on anti-Ro/La positivity was seen.
Eleven patients were therapy naive, whereas five patients had received prior treatment for MALT lymphoma. One patient had been administered rituximab, one had been administered rituximab plus doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP), two had undergone eradication of HP followed by treatment with 2CdA or CHOP and radiation, and one patient had only been irradiated. The time span between prior treatment and inclusion in the study was between 14 and 58 months ([Table 1]).
A total of 69 cycles were administered to our patients (median, four cycles; range, two to six). All except three patients received treatment as scheduled: one refused additional therapy after two courses while in CR, and another two (who were in PR) discontinued for personal reasons after three and four cycles, respectively.
Tolerance of therapy was excellent, and was comparable with data reported in the literature for GI cancers. The most common adverse effects were transient sensory neuropathy WHO grade 2 in eight patients (50%), three patients (19%) suffered from nausea/emesis WHO grade 2, two patients (12.5%) had short-lasting and self-limited hypertension starting immediately after treatment, and three patients (19%) complained of slight dizziness.
Hematologic side effects were virtually absent in our patients, with five patients developing anemia (four occurrences of WHO grade 2 and one occurrence of WHO grade 1), one patient developing leukocytopenia WHO grade 2, and one patient developing thrombocytopenia WHO grade 2.
Application of L-OHP induced objective responses in 15 of 16 patients (94%), with nine patients (56%) achieving CR and six patients (38%) achieving PR, whereas one patient had stable disease. The median number of cycles for reaching CR was four cycles (range, two to six). One patient with lymphoma of the colon, who refused additional treatment for personal reasons while in PR after four cycles, was referred to additional radiotherapy, which resulted in CR.
After a median follow-up of 19 months as calculated from initiation of therapy (range, 13 to 22 months), all patients are alive. Twelve patients are in ongoing remission, whereas three have experienced relapse or progression. One patient developed a systemic relapse 12 months after achieving CR, whereas two experienced progression 4 and 6 months after PR ([Table 1]), including one patient who had been pretreated with R-CHOP.
Sufficient material for genetic analysis was available in all of our patients. In total, genetic aberrations were detected in 11 of 16 patients (69%). Four of these patients had t(11;18)(q21;q21), two had t(14;18)(q32;q21) involving IGH/MALT1, two had trisomy 18, and one patient each had trisomy 3 and trisomy 3 along with trisomy 18. No correlation between clinical outcome and genetic changes could be found ([Table 1]).
DISCUSSION
Various chemotherapeutic regimens have been studied for treatment of MALT lymphoma, but no standard chemotherapy has been defined so far. Although results were promising in all series reported to date[6-9] with excellent response rates especially with 2CdA and fludarabine-containing regimens, application of these nucleoside analogs might be associated with immunosuppression caused by elimination of T cells for a prolonged time.
This is the first study to investigate the potential of L-OHP for treatment of patients with MALT lymphoma, which has shown potential activity in various types of lymphoma.[13-15] As could be expected, toxicities were mild, with reversible sensory neuropathy as the most common adverse event (50% of patients); hematologic adverse effects were virtually absent. Our data clearly indicate that L-OHP is highly active in inducing remissions in this cohort of patients, with an overall objective response rate of 94%. Nine of our 16 patients achieved a CR (56%), and six achieved PR (38%). This high response rate is especially noteworthy, given that the majority of patients had MALT lymphoma of extragastric origin (12 of 16 patients) with disseminated disease in six of 12 patients (50%). Although a response rate of 100% has been reported in patients with fludarabine/mitoxantrone in localized extragastric MALT lymphoma,[8] the response rates in other studies were lower for extragastric versus gastric MALT lymphomas,[7,9] especially in more advanced disease. The fact that chemotherapy in fact is highly effective in patients with localized extragastric disease, as also described by Zinzani et al,[8] is also underscored by our findings. Recent data have demonstrated a high (systemic) relapse rate with local therapies[5] and have shown that the application of chemotherapy does not impair outcome in localized disease.[19] Therefore, inclusion of patients with localized disease in studies of chemotherapeutic agents is justified—even more so because MALT lymphoma is an extremely indolent disease with the potential for salvage therapy if local nonresponse occurs.
The predominance of extragastric MALT lymphoma in our series of consecutively enrolled patients, however, is not due to an investigator-associated selection bias, but reflects the referral pattern at our institution during the respective time span. Although we have no definite explanation for this fact, one might hypothesize that a substantial percentage of patients with gastric MALT lymphoma of localized stages are not referred to hematology/oncologic centers, but undergo HP eradication prescribed by gastroenterologists or general practitioners, and are sent to specialized centers only if no response occurs or they experience dissemination or relapse.
The high response rate along with the low rate of adverse effects and the convenient schedule application (ie, one intravenous infusion during 2 hours every 21 days) make L-OHP a promising candidate for treatment of patients with MALT lymphoma. The study, however, was designed as a proof-of-principle investigation for the activity of L-OHP, and not to assess the long-term outcome in terms of relapse rate and survival after L-OHP as a result of the highly indolent nature of the disease. In a retrospective analysis of 108 patients, Thieblemont et al[20] found the median survival was not reached after a median follow-up time of 52 months, and noted a median time to progression of 4.9 years in extra-GI MALT and 8.9 years in GI-MALT lymphomas. In view of this, a median follow-up time of 19 months in our series is short and does not allow for estimation of long-term outcome of our patients. All patients included in our study are alive at the time of analysis, and three of 16 (19%) patients have experienced relapse or progression. One patient experienced relapse with systemic disease 12 months after reaching CR, whereas two patients with initially disseminated disease experienced progression 4 and 6 months after PR, respectively. One patient had been pretreated with R-CHOP, whereas the other two patients were therapy naive. Given the usually indolent clinical course of MALT lymphoma and the time to progression obtained in studies with a longer available follow-up, this time span appears to be relatively short. Two of these patients, however, had underlying Sjogren's syndrome, and neither clinical symptoms nor serologic changes were affected by L-OHP administration in any of our patients with Sjogren's syndrome.
Taken together, L-OHP was able to induce objective responses in 15 of 16 patients investigated in our series and appears to be a highly effective and nontoxic treatment for patients with MALT lymphoma. Larger series with longer follow-up are needed before we can judge whether these remissions are durable.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
Isaacson P, Wright DH: Malignant lymphoma of mucosa-associated lymphoid tissue: A distinctive type of B-cell lymphoma. Cancer 52:1410-1416, 1983
Isaacson PG, Müller-Hermelink HK, Piris MA, et al: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In Jaffe ES, Harris NL, Stein H, et al (eds): World Health Organization Classification of Tumours: Pathology and Genetics—Tumours of Haemopoietic and Lymphoid Tissues. Lyon, France, IARC Press, 2001, pp 157-160
Du MQ, Diss TC, Dogan A, et al: Clone specific PCR reveals wide dissemination of gastric MALT lymphoma to the gastric mucosa. J Pathol 192:488-493, 2000
Raderer M, Vorbeck F, Formanek M, et al: Importance of extensive staging in patients with mucosa associated lymphoid tissue (MALT)-type lymphoma. Br J Cancer 83:454-457, 2000
Wenzel C, Fiebiger W, Dieckmann K, et al: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue of the head and neck area: High rate of disease recurrence following local therapy. Cancer 97:2236-2241, 2003
Hammel P, Haioun C, Chaumette M, et al: Efficacy of single-agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue lymphoma with prominent gastric expression. J Clin Oncol 13:2524-2529, 1995
Jaeger G, Neumeister P, Brezinschek R, et al: Treatment of extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue-type with cladribine: A phase II study. J Clin Oncol 20:3872-3877, 2002
Zinzani PL, Stefoni V, Musuraca G, et al: Fludarabine-containing chemotherapy as frontline treatment of nongastrointestinal mucosa-associated lymphoid tissue lymphoma. Cancer 100:2190-2194, 2004
W?hrer S, Drach J, Hejna M, et al: Treatment of extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT lymphoma) with mitoxantrone, chlorambucil and prednisone (MCP). Ann Oncol 14:1758-1761, 2003
Raderer M, Jaeger G, Brugger S, et al: Rituximab for treatment of advanced extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue. Oncology 65:306-310, 2003
Conconi A, Martinelli G, Thieblemont C, et al: Clinical activity of rituximab in extranodal marginal zone B-cell lymphoma of MALT-type. Blood 102:2741-2745, 2003
Culy CR, Clemett D, Wiseman LR: Oxaliplatin: A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs 60:895-924, 2000
Germann N, Brienza S, Rotarski M, et al: Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients. Ann Oncol 10:351-354, 1999
Machover D, Delmas-Marsalet B, Misra SC, et al: Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx) as salvage treatment for patients with initially refractory or relapsed non-Hodgkin's lymphoma. Ann Oncol 12:1439-1443, 2001
Chau I, Webb A, Cunningham D, et al: An oxaliplatin-based chemotherapy in patients with relapsed or refractory intermediate and high-grade non-Hodgkin's lymphoma. Br J Haematol 115:786-792, 2001
Radaszkiewicz T, Dragosics B, Bauer P: Gastrointestinal malignant lymphomas of the mucosa associated lymphoid tissue: Factors relevant to prognosis. Gastroenterology 102:1628-1638, 1992
Streubel B, Simonitsch-Klupp I, Müllauer L, et al: Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 18:1722-1726, 2004
Cheson B, Horning S, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253, 1999
Raderer M, Streubel B, Woehrer S, et al: High relapse rate in patients with MALT lymphoma warrants life-long follow up. Clin Cancer Res 11:3349-3352, 2005
Thieblemont C, Bastion Y, Berger F, et al: Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: Analysis of 108 patients. J Clin Oncol 15:1624-1630, 1997(Markus Raderer, Stefan W?)
Center of Excellence in Clinical and Experimental Oncology, Vienna, Austria.
ABSTRACT
PURPOSE: Various chemotherapeutic regimens have been applied for treatment of mucosa-associated lymphoid tissue (MALT) lymphoma, but no standard regimen has been identified to date. In view of the activity of oxaliplatin (L-OHP) in various types of lymphoma, we performed a phase II study to evaluate the activity of L-OHP for treatment of MALT lymphoma. The primary objective of this study was to determine the objective response rate according to WHO standard criteria.
PATIENTS AND METHODS: A total of 16 patients with MALT lymphoma of various sites of origin (four of the ocular adnexa, five of the salivary glands, three of the stomach, two of the lung, and one of the colon and the breast) were administered L-OHP at a dose of 130 mg/m2 infused during 2 hours every 3 weeks. Restaging was performed every two cycles; treatment was continued until complete remission (CR) or for a maximum of six cycles in responders.
RESULTS: Sixty-five cycles were administered (median, four; range, two to six); toxicity consisted of transient sensory neuropathy in eight patients and nausea/emesis WHO grade 2 in two patients, whereas hematologic adverse effects (thrombocytopenia and leukocytopenia grade 2) occurred in only one patient each. Fifteen patients responded to chemotherapy, with nine achieving CR (56%), six (37.5%) achieving partial response, and one achieving stable disease; the median time to response was 4 months (range; 2 to 4 months).
CONCLUSION: These data suggest L-OHP is a highly active agent for treatment of MALT lymphoma. However, a longer follow-up is needed to judge whether these remissions are durable.
INTRODUCTION
Extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma) was initially defined by Isaacson and Wright,[1] and has been incorporated as a distinct entity into the recent WHO classification.[2] The large majority of occurrences are diagnosed in the stomach, but MALT lymphoma may arise in virtually any organ of the human body.[2] Because MALT lymphoma was thought to be a strictly localized disease, local treatment approaches, including surgery and radiation predominantly, were applied in the past. However, the finding of intraorgan[3] and systemic dissemination in a large percentage of patients,[4] as well as high relapse rates despite excellent local control with radiotherapy,[5] have resulted in attempts to evaluate systemic approaches.
At present, there is no chemotherapeutic standard treatment for patients with MALT lymphoma either presenting with disseminated disease or with relapsing/refractory disease after local treatment or after eradication of Helicobacter pylori (HP). Various chemotherapies have been tested, including alkylating agents such as cyclophosphamide or chlorambucil,[6] the nucleoside analogs cladridine[7] (2CdA) or fludarabine, the latter in combination with mitoxantrone,[8] as have combination regimens including cyclophosphamide, vincristine, and prednisone,[8] or mitoxantrone, chlorambucil, and prednisone.[9] In addition, two studies with the CD20 antibody rituximab have been reported in the literature.[10,11] However, only limited data obtained in prospective trials of chemotherapy exist. Thus, studies to evaluate the potential of new chemotherapeutic approaches in patients with advanced MALT lymphoma are justified.
Oxaliplatin (L-OHP) is a new platinum derivative of the diaminocyclohexamine family.[12] In terms of adverse effects as well as cytotoxic activity, it is substantially different from both cisplatin and carboplatin. In vitro data initially have identified it as active in a variety of solid tumors including GI cancers, and it has become part of standard therapy for advanced colorectal carcinoma.
Given that platinum compounds are applied in the treatment of various types of malignant lymphomas, L-OHP has also been investigated for treatment of patients with lymphoma. In a single-center study, Germann et al[13] found L-OHP to be active in patients with relapsed/refractory lymphomas of various histologies, resulting in an objective response rate of 40% when administered as single-agent therapy. When incorporated into a regimen of dexamethasone, high-dose cytarabine, and oxaliplatin, a response rate of 73% (53% complete remission [CR] and 20% partial remission [PR]) was found in 15 patients with lymphomas initially refractory or relapsing after therapy who were treated in a French study.[14] Comparable results were obtained by a British study group[15] using dexamethasone, high-dose cytarabine, and oxaliplatin in 24 patients with various types of lymphoma who experienced treatment failure to prior cytotoxic chemotherapy (response rate, 50%).
Because Germann et al[13] have included two patients with pretreated MALT lymphoma who achieved a PR after L-OHP treatment[12] and because of the excellent tolerance of the agent, we performed a prospective phase II study to investigate the activity of L-OHP in a larger cohort of patients with MALT lymphoma.
PATIENTS AND METHODS
Patients with histologically verified extranodal marginal zone B-cell lymphoma of MALT according to the WHO definition[2] without signs of transformation to diffuse large B-cell lymphoma were enrolled onto this prospective phase II study.
Patients with newly diagnosed MALT lymphoma or those experiencing relapse or progression after prior therapy were eligible. An interval of at least 8 weeks between completion of prior chemotherapy or radiation and initiation of treatment with L-OHP was required. For gastric lymphoma, patients with disease dissemination beyond the stomach were eligible immediately, whereas patients undergoing eradication of HP as initial therapy had to be refractory to antibiotic treatment for inclusion in the study. In such patients, progression of the disease or persistence of lymphoma without signs of regression for a minimum time span of 12 months after successful eradication of HP had to be present for study inclusion. Only patients aged older than 18 years with a WHO performance status 2 were eligible for study entry, and adequate renal (serum creatinine < 1.5 mg/dL), liver (total bilirubin < 2.0 mg/dL and AST level < 2x the upper limit of normal), and bone marrow (leukocyte count > 3,500/μL, platelet count > 100,000/μL) functions were also prerequisites for study entry. Patients with severe concomitant diseases, including a history of another malignancy, florid infections, psychiatric disorders, or peripheral neuropathies were not eligible. In female patients of childbearing age, a pregnancy had to be excluded before inclusion in the trial, and patients were required to use adequate contraception during the entire duration of treatment.
All patients gave written informed consent according to institutional guidelines before study entry, and application of L-OHP to patients with MALT lymphoma was approved by the local ethical committee.
All patients underwent extensive staging before initiation of therapy, consisting of ophthalmologic examination, otorhinolaryngologic investigation including sonography of the salivary glands or magnetic resonance imaging, if indicated, gastroscopy with multiple biopsies, endosonography of the upper GI tract, enteroclysis, colonoscopy, computed tomography of thorax and abdomen, and bone marrow biopsy. Staging was performed according to the Ann Arbor staging system as modified by Radaskiewicz et al[16] for gastric lymphoma. This system was applied because recently published series on extranodal lymphomas have adhered to this concept, and it enables staging of both gastrointestinal as well as extra-GI MALT lymphomas.
In all patients, routine assessment of MALT lymphoma–associated genetic aberrations was performed on biopsy samples. The presence of t(11;18)(q21;q21) was evaluated by reverse transcriptase polymerase chain reaction, whereas t(14;18)(q32;q21) involving IGH/MALT1, t(1;14)(p22;q32), and trisomies 3 and 18 were assessed by fluorescent in situ hybridization, as published previously.[17]
L-OHP was administered by intravenous infusion during 2 hours, repeated every 21 days. Routine premedication consisted of 8 mg intravenous dexamethasone along with an intravenous 5-hydroxytryptamine-3 antagonist administered immediately before application of chemotherapy. L-OHP (Eloxatin) was provided free of charge by Sanofi Synthelabo, Vienna, Austria.
CBCs were evaluated immediately at the start of each cycle and 2 weeks later. For a persisting nadir of the WBCs 3.0 x109/L (or neutrophiles < = 1.0 x109/L) and/or platelets 100 x109/L, the next treatment cycle was delayed 1 week until normal values were achieved. Restaging including computed tomography scan of thorax and abdomen, endosonography, and gastroscopy with histologic reassessment for gastric lymphoma and additional radiologic methods such as magnetic resonance imaging of the salivary glands for parotid lymphoma was performed every two cycles, and treatment was continued in the absence of progressive disease for a maximum of six cycles. For CR after the first reassessment, therapy was continued for and additional two courses up to a total of four. Assessment of response was performed according to standard guidelines,[18] and the times to relapse and failure-free interval were calculated from the first time of documented remission; follow-up time was calculated from the first application of oxaliplatin. For lymphoma restricted to the stomach/GI tract, histologic assessment of biopsy specimens served as the ultimate gold standard.
The primary end point of the study was the objective response rate induced by treatment with L-OHP in patients with MALT lymphoma (ie, rate of PRs and CRs according to Cheson et al,[18] whereas tolerance of chemotherapy in this cohort of patients was the secondary end point.) On the basis of the hypothesis of an expected response rate between 40% and 60%, the planned number of patients for inclusion in the study was 16 according to the Simon rule.[19]
RESULTS
A total of 16 consecutive patients with histologically verified MALT lymphoma according to the recent WHO classification[2] were eligible for inclusion and were enrolled onto the study. Nine patients were female and seven were male, and the median age was 66 years (range, 35 to 74 years). Five patients had lymphoma originating in the salivary glands, four in the ocular adnexa, three in the stomach, two in the lung, and one patient each had MALT lymphoma of the breast and the colon (patient characteristics are listed in [Table 1]). Nine of our 16 patients had Sj?gren's syndrome with respective clinical symptoms and serologic changes. No influence of treatment with L-OHP on the autoimmune disease was seen in our patients, neither in terms of clinical symptoms nor in terms of serologic changes; levels of rheumatoid factor, complement factor C4, and antinuclear antibody titer remained unchanged, and no influence on anti-Ro/La positivity was seen.
Eleven patients were therapy naive, whereas five patients had received prior treatment for MALT lymphoma. One patient had been administered rituximab, one had been administered rituximab plus doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP), two had undergone eradication of HP followed by treatment with 2CdA or CHOP and radiation, and one patient had only been irradiated. The time span between prior treatment and inclusion in the study was between 14 and 58 months ([Table 1]).
A total of 69 cycles were administered to our patients (median, four cycles; range, two to six). All except three patients received treatment as scheduled: one refused additional therapy after two courses while in CR, and another two (who were in PR) discontinued for personal reasons after three and four cycles, respectively.
Tolerance of therapy was excellent, and was comparable with data reported in the literature for GI cancers. The most common adverse effects were transient sensory neuropathy WHO grade 2 in eight patients (50%), three patients (19%) suffered from nausea/emesis WHO grade 2, two patients (12.5%) had short-lasting and self-limited hypertension starting immediately after treatment, and three patients (19%) complained of slight dizziness.
Hematologic side effects were virtually absent in our patients, with five patients developing anemia (four occurrences of WHO grade 2 and one occurrence of WHO grade 1), one patient developing leukocytopenia WHO grade 2, and one patient developing thrombocytopenia WHO grade 2.
Application of L-OHP induced objective responses in 15 of 16 patients (94%), with nine patients (56%) achieving CR and six patients (38%) achieving PR, whereas one patient had stable disease. The median number of cycles for reaching CR was four cycles (range, two to six). One patient with lymphoma of the colon, who refused additional treatment for personal reasons while in PR after four cycles, was referred to additional radiotherapy, which resulted in CR.
After a median follow-up of 19 months as calculated from initiation of therapy (range, 13 to 22 months), all patients are alive. Twelve patients are in ongoing remission, whereas three have experienced relapse or progression. One patient developed a systemic relapse 12 months after achieving CR, whereas two experienced progression 4 and 6 months after PR ([Table 1]), including one patient who had been pretreated with R-CHOP.
Sufficient material for genetic analysis was available in all of our patients. In total, genetic aberrations were detected in 11 of 16 patients (69%). Four of these patients had t(11;18)(q21;q21), two had t(14;18)(q32;q21) involving IGH/MALT1, two had trisomy 18, and one patient each had trisomy 3 and trisomy 3 along with trisomy 18. No correlation between clinical outcome and genetic changes could be found ([Table 1]).
DISCUSSION
Various chemotherapeutic regimens have been studied for treatment of MALT lymphoma, but no standard chemotherapy has been defined so far. Although results were promising in all series reported to date[6-9] with excellent response rates especially with 2CdA and fludarabine-containing regimens, application of these nucleoside analogs might be associated with immunosuppression caused by elimination of T cells for a prolonged time.
This is the first study to investigate the potential of L-OHP for treatment of patients with MALT lymphoma, which has shown potential activity in various types of lymphoma.[13-15] As could be expected, toxicities were mild, with reversible sensory neuropathy as the most common adverse event (50% of patients); hematologic adverse effects were virtually absent. Our data clearly indicate that L-OHP is highly active in inducing remissions in this cohort of patients, with an overall objective response rate of 94%. Nine of our 16 patients achieved a CR (56%), and six achieved PR (38%). This high response rate is especially noteworthy, given that the majority of patients had MALT lymphoma of extragastric origin (12 of 16 patients) with disseminated disease in six of 12 patients (50%). Although a response rate of 100% has been reported in patients with fludarabine/mitoxantrone in localized extragastric MALT lymphoma,[8] the response rates in other studies were lower for extragastric versus gastric MALT lymphomas,[7,9] especially in more advanced disease. The fact that chemotherapy in fact is highly effective in patients with localized extragastric disease, as also described by Zinzani et al,[8] is also underscored by our findings. Recent data have demonstrated a high (systemic) relapse rate with local therapies[5] and have shown that the application of chemotherapy does not impair outcome in localized disease.[19] Therefore, inclusion of patients with localized disease in studies of chemotherapeutic agents is justified—even more so because MALT lymphoma is an extremely indolent disease with the potential for salvage therapy if local nonresponse occurs.
The predominance of extragastric MALT lymphoma in our series of consecutively enrolled patients, however, is not due to an investigator-associated selection bias, but reflects the referral pattern at our institution during the respective time span. Although we have no definite explanation for this fact, one might hypothesize that a substantial percentage of patients with gastric MALT lymphoma of localized stages are not referred to hematology/oncologic centers, but undergo HP eradication prescribed by gastroenterologists or general practitioners, and are sent to specialized centers only if no response occurs or they experience dissemination or relapse.
The high response rate along with the low rate of adverse effects and the convenient schedule application (ie, one intravenous infusion during 2 hours every 21 days) make L-OHP a promising candidate for treatment of patients with MALT lymphoma. The study, however, was designed as a proof-of-principle investigation for the activity of L-OHP, and not to assess the long-term outcome in terms of relapse rate and survival after L-OHP as a result of the highly indolent nature of the disease. In a retrospective analysis of 108 patients, Thieblemont et al[20] found the median survival was not reached after a median follow-up time of 52 months, and noted a median time to progression of 4.9 years in extra-GI MALT and 8.9 years in GI-MALT lymphomas. In view of this, a median follow-up time of 19 months in our series is short and does not allow for estimation of long-term outcome of our patients. All patients included in our study are alive at the time of analysis, and three of 16 (19%) patients have experienced relapse or progression. One patient experienced relapse with systemic disease 12 months after reaching CR, whereas two patients with initially disseminated disease experienced progression 4 and 6 months after PR, respectively. One patient had been pretreated with R-CHOP, whereas the other two patients were therapy naive. Given the usually indolent clinical course of MALT lymphoma and the time to progression obtained in studies with a longer available follow-up, this time span appears to be relatively short. Two of these patients, however, had underlying Sjogren's syndrome, and neither clinical symptoms nor serologic changes were affected by L-OHP administration in any of our patients with Sjogren's syndrome.
Taken together, L-OHP was able to induce objective responses in 15 of 16 patients investigated in our series and appears to be a highly effective and nontoxic treatment for patients with MALT lymphoma. Larger series with longer follow-up are needed before we can judge whether these remissions are durable.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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