ALBERT

Description: 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.

Description: T(11;18)(q21;q21) is the most common structural abnormality in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) leading to the fusion of the apoptosis inhibitor-2 (API2) gene and the MALT lymphoma-associated translocation (MALT1) gene. In 2 patients with MALT lymphoma of the liver and skin, respectively, t(14;18)(q32;q21) was observed by cytogenetic analysis. Subsequent fluorescence in situ hybridization (FISH) studies disclosed that the immunoglobulin heavy-chain locus (IGH) and the MALT1 gene were rearranged by this translocation. In order to screen a large series of MALT lymphomas for this aberration, a 2-color interphase FISH assay was established. Among a total of 66 cases, t(14;18)(q32;q21) involving IGH and MALT1 was detected in MALT lymphomas of the liver (4 of 4), skin (3 of 11), ocular adnexa (3 of 8), and salivary gland (2 of 11), but did not occur in MALT lymphomas of the stomach (n = 10), intestine (n = 9), lung (n = 7), thyroid (n = 4), or breast (n = 2). In total, 12 of 66 (18%) MALT lymphomas harbored t(14;18)(q32;q21); 7 additional cases of splenic marginal zone lymphoma tested negative. All of the 12 MALT lymphomas featuring the t(14;18)(q32;q21) were negative for t(11;18)(q21;q21) by reverse transcriptase–polymerase chain reaction (RT-PCR). However, trisomy 3 and/or 18 was found in 4 of 12 cases, suggesting that the t(14;18)(q32;q21) does not occur as the sole genetic abnormality. This study identifies IGH as a new translocation partner of MALT1 in MALT lymphomas, which tend to arise frequently at sites other than the gastrointestinal tract and lung. In contrast to t(11;18)(q21;q21)+ MALT lymphomas, those with t(14;18)(q32;q21) may harbor additional genetic abnormalities.

Description: Background: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We therefore evaluated the activity and safety of B in combination with R and dexamethasone (BORID) in patients with relapsed and refractory MCL (phase II trial). Methods: A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) achieving a response received 4 additional doses of R as maintenance (every 8 weeks). Pts with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) were eligible. Results: We have completed enrollment of 16 pts (median age, 67 years; range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6, prior rituximab in 88%; thalidomide in 50%; high-dose therapy in 31%; a fludarabine-containing regimen in 31%). Median time between start of frontline therapy and study inclusion was 42 months (range, 11 to 98 months). Severe adverse events (〉 grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts) and vasculitic skin infiltrates in 3 pts. Thrombopenia (〈 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Overall response rate was 69% (11 of 16 pts), with 6 pts achieving a CR (38%; confirmed by PET-scan in 5 pts) and 5 pts reaching a PR. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. Remission status appeared to be associated with progression-free survival (PFS): Patients in CR had longer PFS (29+, 24+, 21+, 12+, 12, and 10+ months) compared to patients in PR (median 8.5 months, range 6 – 15). Conclusions: BORID has promising activitiy (69% overall response rate; CR rate 38%) and managable toxicity in this patient population with predominantly heavily pretreated MCL. Achievement of a CR emerged as an important factor for sustained disease control. Further evaluation of this regimen, in particular in pts at an earlier phase of the disease, is warranted.

Description: Bortezomib (B) belongs to a new class of anti-cancer agents, the proteasome inhibitors, and has documented activity in multiple myeloma and mantle cell lymphoma (MCL). Preclinical studies suggest that B has synergistic activity with rituximab (R), which provides a rationale for the exploration of treatment combinations. We have initiated a phase II study in relapsed/chemotherapy refractory MCL to evaluate the activity and safety of B in combination with R and dexamethasone (BORID). A treatment cycle consists of B at 1.3 mg/m2 administered on days 1, 4, 8, and 11, R at 375 mg/m2 administered on day 1, and dexamethasone 40 mg orally on days 1 to 4. Cycles are repeated every 3 weeks for a total of 6 treatment cycles. Patients (pts) with progressive MCL after at least one prior line of therapy (including CHOP or a CHOP-like regimen) are eligible. We have now enrolled 14 pts at a median age of 69 years (range, 48 to 75 years) after a median of 3 lines of prior therapies (range, 1 to 6) including R in 12 pts, high-dose therapy in 4 pts, and thalidomide in 7 pts. Median time between start of frontline therapy and study inclusion was 43 months (range, 11 to 98 months). Severe adverse events (〉 grade II) included infections (herpes zoster in 2 pts, bacterial pneumonia, mucosal candidiasis), peripheral neuropathy (3 pts), fatigue (2 pts), vasculitic skin infiltrates in 3 pts, and hyponatremia in 1 pt. Thrombopenia (〈 50 G/L) occured in 2 pts. All adverse events were managable by standard means of supportive care and prolongation of the treatment interval between cycles. Of 12 pts evaluable for efficacy, 9 have achieved a response (3 CR, 6 PR), and 2 pts experienced stable disease. Pts in CR were also negative for disease activity by PET scanning. Skin infiltrates (histologically proven T-cell infiltrates) preceded achievement of CR in 2 pts. All 3 pts who achieved a CR are still progression-free at 12 months after treatment initiation. Among pts in PR, 3 pts have relapsed (progression-free survival 14, 11, and 6 months, respectively), and 3 pts are still progression-free beyond 6 months from initiation of treatment. In summary, the BORID treatment regimen has promising activitiy and managable toxicity in patients with heavily pretreated MCL, and development of a vasculitic rash may be an early indicator of a favorable and durable response.

Description: Peripheral T-cell lymphoma is a rare heterogeneous disease with generally poor outcome. Known risk factors include the International Prognostic Index (IPI) and b2 microglobulin. However, there is little information on molecular risk factors. In this single center analysis we have prospectively studied the prognostic value of a clonal T-cell receptor rearrangement (TCR) determined by conventional PCR for the γTCR (sensitivity 1 in 102) from DNA from peripheral blood MNC. Thirty nine consecutive patients diagnosed between 1987 and 2006 were assessed for clonality at diagnosis. Patient characteristics: Median age 53 years (range 28–89). M:F = 29 vs. 10. Histological diagnosis included: PTCL-NOS 7 (18%); Large cell 1 (2.5%); Large + medium-sized 5 (13%); Pleomorphic 7 (18%); Small cell 3 (8%); Small+medium mixed cell 1 (2.5%); Lennert’s type 4 (10%); Hepatosplenic 3 (8%); Intestinal 4 (10%); Kimura’s disease: 1 (2.5%); AILD: 3 (8%). Assessment of γTCR showed monoclonality in 24 (62%) and polyclonality in 15 (38%) patients. Patients with a monoclonal TCR had higher clinical stages, higher LDH levels, higher IPI scores, and higher ß2 microglobulin levels. Clinical stage: CS I–III (clonal 42%; polyclonal 58%) vs. CS IV (clonal 93%; polyclonal 7%). LDH above 240 U/L (clonal 78%; polyclonal 22%). IPI 0,1 (clonal 44%; polyclonal 56%), IPI 2 (clonal 75%; polyclonal 25%), IPI 3 (clonal 87%; polyclonal 13%), IPI 4,5 (clonal 60%; 40%). ß2 microglobulin above 2 mg/L (clonal 68%; polyclonal 32%). Patients with a clonal TCR tended to be older (57 vs. 49 yrs.). No major differences were found for age and sex. Induction treatment consisted of polychemotherapy (CHOP-like=34), prednisone (1), radiation (1). 3 patients received no therapy. Nine patients received subsequent involved field radiation and 6 pts. had an autologous stem cell transplant. Significant differences were observed in terms of disease outcome: The presence of a clonal γTCR (n=24) was associated with low clinical remission rates: CR 38%, PR 21%, SD 8%, PD 33%, relapse rate 38%. Remission rates in patients with polyclonal rearrangements (n=15) were: CR 66%, PR 20%, SD 7%, PD 1%, relapse rate 47%. The estimated 3-year overall survival for the monoclonal group was 26% vs. 69% for the polyclonal group (P=0.01). Importantly, patients with CS I–III and a monoclonal γTCR rearrangement (n=10) had a similarly poor survival when compared to the monoclonal group with CS IV (n=14) (18 months vs. 12 months; P=0.23). This indicates that γTCR positivity is of particular predictive value in patients with CS I–III. The data from this unique cohort suggest that γTCR-PCR is a useful prognostic tool in patients with peripheral T-cell lymphoma. Figure Figure

Description: We evaluated a treatment strategy targeting both lymphoma cells (by rituximab) and the microenvironment (by thalidomide) in 16 patients with relapsed/refractory mantle cell lymphoma (MCL). Rituximab was administered at 375 mg/m2 for 4 weekly doses concomitantly with thalidomide (200 mg daily, with a dose increment to 400 mg on day 15), which was continued as maintenance therapy until progression/relapse. Thirteen patients (81%) experienced an objective response, with 5 complete responders (31%). Median progression-free survival (PFS) was 20.4 months (95% confidence interval [CI], 17.3-23.6 months), and estimated 3-year survival was 75%. In patients achieving a complete response, PFS after rituximab plus thalidomide was longer than PFS after the preceding chemotherapy. Severe adverse events included 2 thromboembolic events and 1 grade IV neutropenia associated with thalidomide. Our results suggest that rituximab plus thalidomide has marked antitumor activity in relapsed/refractory MCL and a low toxicity profile, which warrants further evaluation in MCL.

Description: Abstract 1770 Bronchial-associated lymphoid tissue (BALT) lymphoma is a distinct subgroup of low grade B-cell extranodal lymphoma. The limited clinical information available in the literature makes it difficult to understand if such an indolent lymphoma may have a clinical outcome different from that observed in other extranodal marginal zone lymphomas. The aim of this study is to collect and analyze clinical characteristics of patients with primary marginal zone malignant lymphoma of the lung principally focusing on diagnosis, treatment modality, outcome and finally to evaluate biological and molecular features which may correlate with clinical behaviour. We collected clinical information and histological material on 73 patients diagnosed with marginal zone lymphoma of the lung from February 1990 to August 2008. Central pathology reviewed all histopathological material and the diagnosis was confirmed in 64 (88%) patients. The retrospective analysis has been conducted on this subset of patients. The majority of them (58/64) had limited disease at diagnosis with a good performance status (0-1) and low prognostic index (IPI 0–2). FISH analysis showed a rearrangement on 18q21 in 12 of cases. Median time from diagnosis to any treatment was 30 days (range 0–773). Twenty patients received only local treatment including definitive surgery or radiotherapy. 52 patients needed additional systemic treatment because of advanced stage or incomplete surgical resection. Most of them (26) received an alkylating containing regimen while only 10 patients were treated with an anthracycline containing regimen and 16/52 received monoclonal antibody in combination with chemotherapy. With a median follow up of 54 months, 17/64 patients (27%) relapsed. The median time to relapse was 28 months (range 1–82). No difference in terms of PFS or OS was observed among patients receiving systemic anthracycline or alkylating containing regimens. No significant correlation with MALT 1 aberrations was found. Clinical results observed in such retrospective study seem to suggest as surgery clearly benefits patients with localized disease. Chemotherapy can be reserved for early aggressive relapse. Systemic treatment could be recommended for patients with advanced stage or with incomplete response after the surgical procedure: when chemotherapy must be considered, alkylating containing regimens seem the best option. Considering data of a “pre-rituximab era”, the role of monoclonal antibodies still needs to be clarified and ongoing trials from IELSG could be helpful on this topic. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points The MALT-IPI was built by using 401 patients in the IELSG-19 randomized trial and validated in an independent set (N = 633). This novel disease-specific index efficiently discriminates patient with good, intermediate, and poor outcomes.

Description: Abstract 958 BACKGROUND: Helicobacter pylori (Hp) infection is associated with the pathogenesis of marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)-type of the stomach, and Hp-eradicating antibiotic therapy is the standard treatment for this lymphoma, with complete remission rates of 60–80%. Hp is also detected in 35% of diffuse large B-cell lymphomas (DLBCL) of the stomach, being more common in cases with concomitant MALT areas with respect to de novo cases (65% vs. 15%). However, the role of Hp-eradicating antibiotic therapy in gastric DLBCL remains to be elucidated, since only rare and small, monoinstitutional retrospective studies are available. Herein, we report the final results of a multicentre phase II trial, the first one in Western countries, addressing the role of Hp-eradicating therapy as exclusive treatment in patients with gastric DLBCL. AIMS: To assess feasibility, activity and efficacy of Hp-eradicating therapy as exclusive treatment for limited-stage DLBCL of the stomach. METHODS: Inclusion criteria were histopathologic diagnosis of DLBCL, with or without concomitant MALT-type areas; Hp-infection assessed by multiple gastric biopsies and/or breath test; stage I-II1 of disease according to Musshoff staging system; perigastric lymph nodes diameter 65 years old. Importantly, unresponsive patients can be safely salvaged with conventional treatment. Registered cases of Hp-associated DLBCL of the stomach will be characterized under pathologic and molecular perspectives to identify parameters useful to distinguish the best candidates for eradicating therapy. Disclosures: No relevant conflicts of interest to declare.