Barbara Kiesewetter

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).

Evaluation of Diffusion-Weighted MRI for Pretherapeutic Assessment and Staging of Lymphoma: Results of a Prospective Study in 140 Patients

Purpose: To determine the value of diffusion-weighted MRI (DWI-MRI) for pretherapeutic imaging of fluorodeoxyglucose (FDG)-avid lymphoma and lymphoma with variable FDG avidity. Experimental Design: Treatment-naïve patients with lymphoma who were referred for whole-body staging were included in this prospective study. Group A included patients with FDG-avid lymphoma (e.g., Hodgkin, diffuse large B-cell, and follicular lymphoma), whereas Group B included patients with lymphoma of variable FDG avidity [e.g., extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)]. All patients underwent DWI-MRI and 18F-FDG- positron emission tomography/computed tomography (PET/CT). Region-based sensitivity and agreement with Ann Arbor staging, relative to the reference standard, were calculated for DWI-MRI, and, in Group B, also 18F-FDG-PET/CT and contrast-enhanced (CE-) CT. Results: In Group A (100 patients), DWI-MRI had a region-based sensitivity of 97%, and with regard to staging, agreed with the reference standard in 94 of 100 patients (κ, 0.92). In Group B (40 patients; 38 MALT lymphomas and 2 small lymphocytic lymphomas/chronic lymphocytic leukemias), DWI-MRI, 18F-FDG-PET/CT, and CE-CT had region-based sensitivities of 94.4%, 60.9%, and 70.7%, respectively. With regard to staging in Group B, DWI-MRI, 18F-FDG-PET/CT, and CE-CT agreed with the reference standard in 37 of 40, 26 of 40, and 24 of 40 patients, with κ values of 0.89, 0.52, and 0.43, respectively. Conclusions: In patients with FDG-avid lymphoma, DWI-MRI seems to be only slightly inferior to 18F-FDG-PET/CT with regard to pretherapeutic regional assessment and staging. In patients with lymphoma subtypes that show a variable FDG avidity (e.g., MALT lymphoma), DWI-MRI seems to be superior to both 18F-FDG-PET/CT and CE-CT. Clin Cancer Res; 20(11); 2984–93. ©2014 AACR.

Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature

Although antibiotic therapy has been established as the standard of care in patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma, much less is known about the value of antibiotic therapy in nongastrointestinal (non-GI) MALT lymphomas. A computerized search (Medline) accompanied by a manual search to identify clinical reports on the topic of antibacterial therapy in patients with non-GI MALT lymphomas was performed. The majority of data were available for MALT lymphoma of the ocular adnexa (OAML) including a total of 131 patients in 4 retrospective studies, 3 prospective series (including 81 patients), and 1 case report. Treatment was exclusively targeting Chlamydophila psittaci (CP), using doxycycline in all but 2 studies. The median follow-up for these studies was 25 months, and both CP-positive as well as CP-negative patients responded. Complete remission was achieved in 23 patients (18%), 36 (27%) had a partial remission, 55 (42%) had stable disease, and 8 patients (6%) had progressive disease accounting for an overall response rate of 45%. In the largest study, a better response was suggested in CP-positive patients. By contrast, only scattered reports could be found for other non-GI localizations, allowing no conclusion about the benefit of antibiotic therapy and probably resulting in a publication bias toward positive cases. Based on these results, antibiotic therapy using doxycycline appears to be a reasonable first-line therapy for patients with OAML. Antibiotics, however, remain experimental for the time being in patients with other non-GI MALT lymphomas. Further preclinical studies as well as large-scale therapeutic trials are warranted to define the role of antibiotic therapy in such patients.

Evaluation of Diffusion-weighted Magnetic Resonance Imaging for Follow-Up and Treatment Response Assessment of Lymphoma: Results of an 18F-FDG-PET/CT-controlled Prospective Study in 64 Patients

Purpose: To determine the value of diffusion-weighted MRI (DWI-MRI) for treatment response assessment in 2-[18F]fluoro-2-deoxy-D-glucose (FDG)–avid lymphoma. Experimental Design: Patients with FDG-avid Hodgkin (HL) or non-Hodgkin lymphoma (NHL) at pretherapeutic 18F-FDG-PET/CT, who had also undergone pretherapeutic whole-body DWI-MRI, were included in this prospective study. Depending on the histologic lymphoma subtype, patients received different systemic treatment regimens, and follow-up DWI-MRI and 18F-FDG-PET/CT were performed at one or more time points, depending on the clinical course. For each follow-up DWI-MRI, region-based rates of agreement, and rates of agreement in terms of treatment response (complete remission, partial remission, stable disease, or progressive disease), relative to the corresponding 18F-FDG-PET/CT, were calculated. Results: Sixty-four patients were included: 10 with HL, 22 with aggressive NHL, and 32 with indolent NHL. The overall region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.4%. For the 51 interim examinations (performed after 1–3 therapy cycles), region-based agreement of DWI-MRI with 18F-FDG-PET/CT was 99.2%, and for the 48 end-of-treatment examinations, agreement was 99.8%. No significant differences, in terms of region-based agreement between DWI-MRI and 18F-FDG-PET/CT, were observed between the three lymphoma groups (HL, aggressive NHL, indolent NHL; P = 0.25), or between interim and end-of-treatment examinations (P = 0.21). With regard to treatment response assessment, DWI-MRI agreed with 18F-FDG-PET/CT in 99 of 102 follow-up examinations (97.1%), with a κ value of 0.94 (P < 0.0001). Conclusions: In patients with FDG-avid lymphoma, DWI-MRI may be a feasible alternative to 18F-FDG-PET/CT for follow-up and treatment response assessment. Clin Cancer Res; 21(11); 2506–13. ©2015 AACR.

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.

Clinicopathologic characteristics and treatment of marginal zone lymphoma of mucosa‐associated lymphoid tissue (MALT lymphoma)

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Clinical activity of everolimus in relapsed/refractory marginal zone B-cell lymphomas: results of a phase II study of the International Extranodal Lymphoma Study Group.

The International Extranodal Lymphoma Study Group coordinated a phase II trial to evaluate the activity and safety of everolimus in marginal zone lymphomas (MZLs). Thirty patients with relapsed/refractory MZLs received everolimus for six cycles or until dose‐limiting toxicity or progression. Median age was 71 years (range, 51–88 years). Twenty patients had extranodal, six splenic, four nodal MZL. Twenty‐four patients had stage III–IV. Median number of prior therapies was two (range 1–5). Seventeen patients had early treatment discontinuation, in most cases due to toxicity. Median number of cycles was 4·5 (range, 1–16). Among the 24 assessable patients, the overall response rate (ORR) was 25% (95% confidence interval: 10–47). Grade 3–4 adverse events were neutropenia and thrombocytopenia (17% of patients, each), infections (17%), mucositis and odontogenic infections (13%) and lung toxicity (3%). The median response duration was 6·8 months (range, 1·4–11·1+). After a median follow‐up of 14·5 months, five deaths were reported: four deaths were due to lymphoma, one was due to toxicity. In an intent‐to‐treat analysis, the projected median progression‐free survival was 14 months. The moderate antitumour activity of everolimus in relapsed/refractory MZLs and the observed toxicity limit its therapeutical applicability in these indolent entities. Lower doses of the drug and, perhaps, different strategies including combination with additional agents need to be explored.

18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance in Lymphoma: Comparison With 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography and With the Addition of Magnetic Resonance Diffusion-Weighted Imaging.

ObjectivesThe aim of this study was to compare 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/magnetic resonance (MR) (with and without diffusion-weighted imaging [DWI]) to 18F-FDG PET/computed tomography (CT), with regard to the assessment of nodal and extranodal involvement, in patients with Hodgkin lymphoma and non-Hodgkin lymphoma, without restriction to FDG-avid subytpes. Materials and MethodsPatients with histologically proven lymphoma were enrolled in this prospective, institutional review board–approved study. After a single 18F-FDG injection, patients consecutively underwent 18F-FDG PET[Fraction Slash]CT and 18F-FDG PET/MR on the same day for staging or restaging. Three sets of images were analyzed separately: 18F-FDG PET/CT, 18F-FDG PET/MR without DWI, and 18F-FDG PET/MR with DWI. Region-based agreement and examination-based sensitivity and specificity were calculated for 18F-FDG PET/CT, 18F-FDG PET/MR without DWI, and 18F-FDG PET/MR DWI. Maximum and mean standardized uptake values (SUVmax, SUVmean) on 18F-FDG PET/CT and 18F-FDG PET/MR were compared and correlated with minimum and mean apparent diffusion coefficients (ADCmin, ADCmean). ResultsThirty-four patients with a total of 40 examinations were included. Examination-based sensitivities for 18F-FDG PET/CT, 18F-FDG PET/MR, and 18F-FDG PET/MR DWI were 82.1%, 85.7%, and 100%, respectively; specificities were 100% for all 3 techniques; and accuracies were 87.5%, 90%, and 100%, respectively. 18F-FDG PET/CT was false negative in 5 of 40 examinations (all with mucosa-associated lymphoid tissue lymphoma), and 18F-FDG PET/MR (without DWI) was false negative in 4 of 40 examinations. Region-based percentages of agreement were 99% (&kgr;, 0.95) between 18F-FDG PET/MR DWI and 18F-FDG PET/CT, 99.2% (&kgr;, 0.96) between 18F-FDG PET/MR and 18F-FDG PET/CT, and 99.4% (&kgr;, 0.97) between 18F-FDG PET/MR DWI and 18F-FDG PET/MR. There was a strong correlation between 18F-FDG PET/CT and 18F-FDG PET/MR for SUVmax (r = 0.83) and SUVmean (r = 0.81) but no significant correlation between ADCmin and SUVmax (18F-FDG PET/CT: r = 0.46, P = 0.65; 18F-FDG PET/MR: r = 0.64, P = 0.53) or between ADCmean and SUVmean (respectively, r = −0.14, P = 0.17 for the correlation with PET/CT and r = −0.14, P = 0.14 for the correlation with PET/MR). Conclusions18F-FDG PET/MR and 18F-FDG PET/CT show a similar diagnostic performance in lymphoma patients. However, if DWI is included in the 18F-FDG PET/MR protocol, results surpass those of 18F-FDG PET/CT because of the higher sensitivity of DWI for mucosa-associated lymphoid tissue lymphomas.

High-dose clarithromycin is an active monotherapy for patients with relapsed/refractory extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT): the HD-K phase II trial

BACKGROUND Clarithromycin displays immunomodulatory and antineoplastic properties. As single agent, this macrolide is associated with tumor responses in anecdotal cases of relapsed/refractory extranodal marginal zone lymphoma (rrEMZL), with a putative dose-dependent effect. Tolerability and activity of high-dose clarithromycin (HD-K) in patients with rrEMZL were addressed in a phase II trial (clinicaltrials.gov NCT01516606). METHODS HIV-negative adults with rrEMZL and at least one measurable/parametrable lesion were enrolled and treated with four courses of oral clarithromycin 2 g/day, days 1-14, every 21 days. Activity (overall response rate, ORR) was the primary end point. RESULTS Twenty-three patients were registered (median age 70 years, range 47-88 years; M:F ratio: 0.27). HD-K was given at greater than or equal to second relapse in 11 patients. Ocular adnexae were the most commonly involved organs. Five patients had hepatitis B virus/hepatitis C virus (HBV/HCV) infections; Helicobacter pylori and Chlamydophila psittaci infections were excluded at the time of patient registration.Tolerability was excellent, even among HBV/HCV-positive patients; only two patients had grade >2 toxicity (nausea). Six patients achieved a complete remission and six a partial response (ORR = 52%; 95% confidence interval 32% to 72%). Age, previous treatment and stage did not influence activity. At a median follow-up of 24 (16-33) months, only two patients with responsive disease experienced relapse, with a 2-year progression-free survival of 56 ± 10%; all patients are alive. CONCLUSIONS HD-K is a safe and active salvage treatment in EMZL patients. This macrolide deserves to be further investigated in EMZL and other lymphoma categories.

Clinical Features, Treatment and Outcome of Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma of the Ocular Adnexa: Single Center Experience of 60 Patients

Background Orbital marginal zone B-cell lymphoma (OAML) constitutes for the most frequent diagnosis in orbital lymphoma. Relatively little data, however, have been reported in larger cohorts of patients staged in a uniform way and no therapy standard exists to date. Material and Methods We have retrospectively analyzed 60 patients diagnosed and treated at our institution 1999–2012. Median age at diagnosis was 64 years (IQR 51–75) and follow-up time 43 months (IQR 16–92). All patients had undergone uniform extensive staging and histological diagnosis was made by a reference pathologist according to the WHO classification. Results The majority of patients presented with stage IE (n = 40/60, 67%), three had IIE/IIIE and the remaining 17 stage IVE. Seven patients with IVE had bilateral orbital disease whereas the others showed involvement of further organs. Treatment data were available in 58 patients. Local treatment with radiotherapy (14/58, 24%) or surgery (3/58, 5%) resulted in response in 82% of patients. A total of 26 patients (45%) received systemic treatment with a response rate of 85%. Nine patients received antibiotics as initial therapy; response rate was 38%. Watchful-waiting was the initial approach in 6/58 patients. In total 28/58 patients (48%) progressed and were given further therapy. Median time-to-progression in this cohort was 20 months (IQR 9–39). There was no difference in time-to-progression after first-line therapy between the different therapy arms (p = 0.14). Elevated beta-2-microglobulin, plasmacytic differentiation, autoimmune disorder and site of lymphoma were not associated with a higher risk for progress. Conclusion Our data underscore the excellent prognosis of OAML irrespective of initial therapy, as there was no significant difference in time-to-progression and response between local or systemic therapy. In the absence of randomized trials, the least toxic individual approach should be chosen for OAML.