Marlene Troch

Assessment of Disease Dissemination in Gastric Compared With Extragastric Mucosa-Associated Lymphoid Tissue Lymphoma Using Extensive Staging: A Single-Center Experience

PURPOSE Molecular data and preliminary clinical findings have suggested mucosa-associated lymphoid tissue (MALT) lymphoma as a multifocal disease in a high percentage of patients. We report our findings with an extensive staging routine applied in patients diagnosed with MALT lymphoma at our institution. PATIENTS AND METHODS A total of 140 consecutive patients (61 with gastric and 79 with extragastric MALT lymphoma) underwent staging according to a standardized protocol. Staging included gastroscopy with multiple biopsies, endosonography of the upper GI tract, computed tomography of thorax and abdomen, lymph node sonography, colonoscopy with multiple biopsies, otorhinolaryngologic assessment, magnetic resonance imaging of salivary and lacrimal glands, and bone marrow biopsy. All lesions suggestive of lymphoma involvement were subjected to biopsy, if accessible, and biopsies were evaluated for MALT lymphoma-specific genetic aberrations by means of reverse transcriptase polymerase chain reaction and/or fluorescent in situ hybridization. RESULTS Fifteen (25%) of 61 patients with gastric MALT lymphoma had multiorgan involvement, with dissemination beyond the GI tract in six patients. By contrast, significantly more patients with extragastric MALT lymphoma had dissemination to another MALT organ (37 of 79 patients, 46%; P = .045). Nine of these 37 patients had dissemination to the stomach. Only three (2%) of 140 patients had bone marrow involvement. Multifocality was significantly associated with t(11;18)(q21;q21) in gastric lymphomas (P = .045) and with trisomy 18 in extragastric lymphomas (P = .011). CONCLUSION Our findings suggest that MALT lymphoma frequently presents as a multifocal disease. Extragastric MALT lymphomas are significantly more prone to dissemination than gastric MALT lymphomas.

A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma)

Mucosa associated lymphoid tissue lymphoma shares certain features with multiple myeloma. In view of this and the activity of lenalidomide in various B-cell lymphomas, we have initiated a phase II study of lenalidomide in patients with mucosa associated lymphoid tissue lymphoma. Patients with histologically verified advanced stages of this lymphoma were included in the study. Treatment consisted of oral lenalidomide 25 mg Days 1–21, with a 7-day break after each cycle. A total of 18 patients were included in the trial: 5 had gastric and 13 had extragastric mucosa associated lymphoid tissue lymphoma, but 2 discontinued therapy during the first course of therapy. In the intent to treat analysis, an overall response rate of 61% was seen (11 of 18; 6 complete and 5 partial remissions). Three patients had stable disease while 2 progressed. Side effects were manageable and included neutropenia (grade III in 3 patients) as the leading hematotoxicity. After a median follow up of 20.3 months, one patient has died from lymphoma while the remaining patients are alive and relapse-free. These data suggest activity of lenalidomide monotherapy in mucosa associated lymphoid tissue lymphoma. The study protocol had been approved by the Ethical Board of the Medical University Vienna (EK-No.: 146/09), and before opening the trial, it had been registered at www.clinicaltrials.gov. (identifier: NCT00923663).

High Efficacy of Concomitant Treatment of Undifferentiated (Anaplastic) Thyroid Cancer with Radiation and Docetaxel

CONTEXT Anaplastic thyroid carcinoma (ATC) is a rare but aggressive solid tumor with a very short survival time even with multimodality treatment. In view of in vitro data and the high rate of p53 mutations in ATC, we have used combined treatment with external beam radiation and docetaxel. OBJECTIVE The objective was to analyze the activity using radiation plus docetaxel. DESIGN The design was a retrospective analysis. SETTING The study was performed in a referral center of a university hospital. PATIENTS A total of six patients with ATC were treated at our institution. INTERVENTION Treatment consisted of standard external beam radiation of 60.0 Gy in 30 fractions along with docetaxel at a flat dose of 100 mg absolute every 3 wk for a total of six cycles starting within the first week of radiation. OUTCOME MEASURE The outcome measure included clinical response and survival. RESULTS Five patients completed radiochemotherapy. One patient has completed radiation but is still on treatment with docetaxel. Four patients achieved complete remission and two partial response. During radiation therapy, four patients developed severe mucositis/stomatitis and two dermatitis, necessitating hospitalization. Two patients developed pneumonia and one urinary tract infection. All patients were hospitalized for a median of 17 d (range, 4-40 d) because of toxicites. After a median follow up of 21.5 months (range, 2-40 months), five patients are alive. CONCLUSION The preliminary data suggest that the combination of radiation and concomitant docetaxel is highly effective in patients with ATC. However, a formal phase II study is needed to assess the therapeutic potential of this combination.

Activity of Rituximab plus Cyclophosphamide, Doxorubicin/Mitoxantrone, Vincristine and Prednisone in Patients with Relapsed MALT Lymphoma

Background: Various chemotherapeutic agents as well as the anti-CD20 antibody rituximab (R) have been tested in patients with mucosa-associated lymphoid tissue (MALT) lymphoma, but no standard chemotherapeutic regimen has emerged so far. Judging from the data obtained in various types of lymphoma, the activity of R appears to be enhanced by combination with chemotherapy. As no data on this topic exist for MALT lymphoma, we have retrospectively analysed our experience with R plus cyclophosphamide, doxorubicin/mitoxantrone, vincristine and prednisone (R-CHOP/R-CNOP) in patients with relapsed MALT lymphoma. Patients and Methods: A total of 26 patients were identified, 15 were administered R-CHOP while 11 patients were given R-CNOP due to age >65 years or pre-existing cardiac conditions. Cycles were repeated every 21 days, and restaging was performed after 4 cycles of therapy. In case of complete remission, 2 further cycles were administered for consolidation while patients achieving partial remission or stable disease after restaging were given 4 further courses. Results: A total of 170 cycles were administered to our patients (median 6, range 2–8). Twenty of the 26 patients (77%) achieved a complete remission and 6 (23%) a partial remission. Toxicities were mainly haematological, with WHO grade III/IV leukocytopenia occurring in 5 patients. After a median follow-up of 19 months (range 10–45), all patients are alive: 22 are in ongoing remission, while 4 have relapsed between 12 and 19 months after treatment. Conclusions: Our data demonstrate a high activity of R-CHOP/R-CNOP in relapsing MALT lymphoma irrespective of prior therapy.

A phase II study of bortezomib in patients with MALT lymphoma

The activity of bortezomib in patients with MALT lymphoma is unclear. This study shows that that bortezomib is active in patients with MALT lymphoma. However, an unexpectedly high rate of toxicities was seen, warranting assessment of combination schedules with bortezomib at a lower dose than given in this study. We have performed a phase II study to evaluate bortezomib in patients with MALT-lymphoma. Sixteen patients entered the trial, 4 had gastric MALT-lymphoma, 7 of the ocular adnexa, one of the colon, and 2 of the parotid, and one patient each the lung and the breast. Bortezomib was given at 1.5 mg/m2 days 1, 4, 8 and 11; repeated every 21 days. The overall response rate was 80% (13/16); 7 patients achieved complete remission (43%), 6 partial response (37%) and 3 stable disease. After a median follow-up of 23 months (range; 8–26), all patients are alive and 4 have relapsed. Fifteen patients required dose reductions due to either neuropathy (7 patients) or diarrhea (8 patients). Bortezomib appears to be active in patients with MALT-lymphoma. However, an unexpectedly high rate of toxicities was seen, warranting assessment of combination schedules with bortezomib at a lower dose than given in our study (ClinicalTrials.govIdentifier: NCT 00373906).

Rituximab plus subcutaneous cladribine in patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a phase II study by the Arbeitsgemeinschaft Medikamentöse Tumortherapie

Currently, there is no standard systemic treatment for extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue. Both rituximab and cladribine have shown some activity in this disease, but the combination has not been tested so far. In view of this, we initiated a phase II study to assess the activity and safety of rituximab and cladribine in patients with histologically verified mucosa-associated lymphoid tissue lymphoma. Treatment consisted of rituximab 375 mg/m2 i.v. day 1 and cladribine 0.1 mg/kg s.c. days 1 – 4 every 21 days. In case of complete remission after two courses, another two cycles of therapy were administered, while patients with a partial response or stable disease were scheduled to receive six cycles of treatment. Out of 40 evaluable patients (14 female, 26 male), 39 received treatment as scheduled while one patient died before initiation of therapy and was rated as having progressive disease in the intent-to-treat analysis. Twenty-one patients had gastric lymphoma, while 19 suffered from extragastric mucosa-associated lymphoid tissue lymphoma. Side effects consisted mainly of hematologic toxicity including leukopenia, lymphopenia, anemia and thrombocytopenia. Twenty-three patients had a complete remission (58%) and nine had a partial remission (23%) for an overall response rate of 81%, while five had stable disease (13%) and two progressed during therapy. After a median follow-up of 16.7 months (interquartile range: 15.9 – 18.7 months), 35 patients are alive (88%) while four patients have died and one patient withdrew consent and did not allow further follow up. Our data demonstrate that rituximab plus cladribine is active and safe in patients with mucosa-associated lymphoid tissue lymphoma.

Chronic autoimmune thyroiditis (Hashimoto's thyroiditis) in patients with MALT lymphoma

BACKGROUND Autoimmune diseases have been implicated in the genesis of MALT lymphoma of various localizations. The development of thyroidal MALT lymphoma has been described as an adverse event in patients suffering from long-standing chronic autoimmune thyroiditis (CAT, Hashimotos thyroiditis). The percentage and possible association between CAT and extrathyroidal MALT lymphoma, however, have not been assessed so far. PATIENTS AND METHODS A retrospective analysis of 80 patients with MALT lymphoma diagnosed and treated at our institution identified a total of 13 patients (16%) with MALT lymphoma suffering from an underlying CAT. Patient characteristics including site of disease, stage, genetic changes and clinical course were assessed and evaluated. RESULTS In total, 10 patients were female and 3 male, with the median age being 57 years (range: 31-80). Four patients suffered from thyroidal lymphoma and nine patients had extrathyroidal lymphoma (four gastric, two orbital, one small intestinal and two salivary gland lymphomas). Three patients had a long-standing history of CAT at diagnosis of MALT lymphoma, while CAT was discovered during staging and clinical work-up of MALT lymphoma in the remaining 10 patients. All 13 patients had localized disease, i.e. stage I or II. Only one of the four patients with gastric MALT lymphoma responded to antibiotic treatment against Helicobacter pylori infection. Genetic aberrations were detected in four patients, two of whom had a t(11;18)(q21;q21) translocation, one patient had trisomies 3 and 18 and one had trisomy 18. CONCLUSION Our findings suggest that CAT is found in patients with not only thyroidal but also nonthyroidal MALT lymphoma. While the nature of our data does not allow for delineation of a direct association between CAT and development of extrathyroidal MALT lymphoma, further prospective studies on this issue are warranted.

Assessment of the role of hepatitis C, Helicobacter pylori and autoimmunity in MALT lymphoma of the ocular adnexa in 45 Austrian patients

Introduction. A recent series from Italy has suggested a pathogenic link between hepatitis C virus and MALT lymphoma of the ocular adnexa. The hypothesis of our study was to prove this concept in Austrian patients with MALT lymphoma of the ocular adnexa. Materials and methods. A total of 45 patients presenting with MALT lymphoma of the ocular adnexa were assessed for the presence of infection with hepatitis A, B and C. Furthermore, extensive staging to evaluate the extent of disease along with analysis of Helicobacter pylori-infection, the presence or absence of autoimmune diseases (AD) and assessment of MALT-lymphoma specific genetic changes was performed. Results. Only 2/45 (4%) patients were tested positive for hepatitis C, while 10/45 (22%) had an underlying AD and 15/39 (38%) had HP infection. Chromosomal aberrations were detected in 19 (54%) of 35 patients analyzed. Disseminated disease was a significant risk factor for relapse (p=0.014). Discussion. Our series suggests that infection with hepatitis C is not a significant contributor to the pathogenesis of ocular adnexal MALT lymphoma in the Austrian population, while a substantial proportion of these patients suffer from autoimmune conditions.

90Y-ibritumomab tiuxetan (Zevalin) in heavily pretreated patients with mucosa associated lymphoid tissue lymphoma

Radioimmunotherapy using 90Y-ibritumomab tiuxetan has predominantly been used in patients with follicular lymphoma, but little is known about its activity in patients with extranodal marginal zone lymphoma of the mucosa associated lymphoid tissue (MALT). A total of six patients progressing/relapsing following conventional therapy for MALT lymphoma were treated with 90Y-ibritumomab tiuxetan at our institution. Two patients had gastric MALT lymphoma, one suffered from orbital MALT lymphoma, and two had cutaneous MALT lymphoma, while one patient had a widely disseminated lymphoma involving the stomach, lungs, lymph nodes, and salivary glands. All patients were at least in third relapse following various forms of therapy including Helicobacter pylori-eradication, radiation, chemotherapy, and application of rituximab. Following two doses of rituximab at 250 mg/m2 at an interval of 1 week, 90Y-ibritumomab tiuxetan was given immediately at a dose of 0.4 mCi/kg body weight. Treatment was well tolerated apart from one episode of pneumonia requiring hospitalization. Four patients developed a complete remission (ongoing now for 4, 16, 23, and 24 months), one patient had a partial response lasting for 5 months, and one patient had stable disease for 13 months. After a follow-up of 9–29 months, all patients are alive. Application of 90Y-ibritumomab tiuxetan is active and safe in heavily pretreated patients with MALT lymphoma.

Clinicopathological aspects of mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland: a retrospective single-center analysis of 28 cases.

In constrast to its gastric counterpart, mucosa‐associated lymphoid tissue (MALT) lymphoma of the parotid gland has not been studied extensively. We analyzed the clinicopathological features and the clinical course of all patients with parotid gland MALT lymphoma diagnosed and treated at our institution.