Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue–type of the orbit and ocular adnexa

Non-Hodgkins lymphomas of the orbit and ocular adnexa (OOA), the majority of which are extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue-type (MALT lymphomas), are a rare disorder. The aim of this study was to evaluate the clinical features and treatment outcomes and complications in patients with MALT lymphoma of OOA. Thirty-seven patients with a histologically verified diagnosis of MALT lymphoma of OOA were included in this retrospective, observational case study. There were 22 (59%) men and 15 (41%) women, with a median age of 44 years (range, 21–80 years). The most common presenting complaint was a slowly growing orbital mass. The stages were IA_E in 74%, IA_EE (bilateral involvement) in 18%, IIIA_E in 6%, and IVA_E in 3%. None of the patients had an elevated value of LHD or ₂-microglobulin. Surgical resection alone was attempted as the sole treatment in two patients, but tumor recurred 19 and 24 months after surgery. Radiotherapy, with a median tumor dose of 3,060 cGy, was administered in 29 patients; all of the patients achieved complete remission, and none of them had severe later complications. Combination chemotherapy alone was employed in three patients with stage IIIA_E or IVA_E. With a median follow-up duration of 21 months, the 3-year overall survival (OS) rate and event-free survival (EFS) rate were 97% and 86%, respectively. Subgroup analysis of the patients with localized disease, who received radiotherapy as an initial treatment modality, revealed that 3-year OS rate and EFS rate were 100% and 93%, respectively. All disease recurrences were documented histologically as MALT lymphoma. In conclusion complete staging evaluation is needed to select an adequate treatment modality. Radiotherapy alone can produce excellent local control and survival in patients with localized MALT lymphoma of OOA. Systemic chemotherapy should be considered in patients with advanced stages or systemic manifestation.Presented in part at the 45th ASH annual meeting, San Diego, CA, December 6–9, 2003.     

Splenic marginal zone lymphoma – a clinicopathological study in a series of 16 patients

Abstract

Splenic marginal zone lymphoma (SMZL), characterized in the WHO classification of lymphoid tumors, is a rare disorder comprising less than 1% of lymphoid neoplasms; only a few series concerning this entity have been published. Although this type of lymphoma is well defined histologically, its histogenesis remains obscure. Moreover, specific biological markers are still lacking and immunophenotype profile is not specific. These and other reasons, such as the existence of cytogenetic subtypes, have led to some authors to suspect that SMZL constitutes a heterogeneous entity. We have analyzed a series of sixteen SMZL cases from four hospitals in our community, from a clinical, biological and pathological point of view. When compared with those reported in the literature, our findings show three main differences: our patients less frequently showed an intrasinusoidal bone marrow infiltration pattern; the presence of a serum monoclonal component was rarely seen; and CD5-positive SMZL cases appear to be more common than previously thought.     

Which test to use to detect Helicobacter pylori infection in patients with low-grade gastric mucosa-associated lymphoid tissue lymphoma?

Helicobacter pylori is involved in the pathogenesis of lymphoma of the gastric mucosa-associated lymphoid tissue (MALT). Because gastric MALT lymphoma is a rare disease, few studies comparing the accuracy of diagnostic tests in this group of patients have been carried out, and only a limited number of tests (essentially histological) were performed. The aim of our study was to compare the results of four different diagnostic methods used to detect H. pylori (histology, culture, polymerase chain reaction, and serology) in a prospective multicenter study. A patient was considered to be H. pylori positive if culture or histology was positive. During the period 1995-2000, a total of 90 patients with low-grade gastric MALT lymphoma were enrolled. Results for the four tests were available for 56 patients (62.2%). Among these patients, the four tests were concordant in 35 cases (62.5%), i.e., were positive in 19 cases (33.9%) and negative in 16 patients (17.8%). Histology (39/40 positive, 97.5%) and serology (38/40 positive, 95.0%) were the most sensitive tests. Polymerase chain reaction (PCR) and culture were positive in 52.5% and 50%, respectively. The cagA gene was detected in 47.4% of the strains.     

Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study

OBJECTIVE: To investigate the safety and efficacy of B cell depletion treatment of patients with active primary Sj?gren's syndrome of short duration (early primary SS) and patients with primary SS and mucosa-associated lymphoid tissue (MALT)-type lymphoma (MALT/primary SS). METHODS: Fifteen patients with primary SS were included in this phase II trial. Inclusion criteria for the early primary SS group were B cell hyperactivity (IgG >15 gm/liter), presence of autoantibodies (IgM rheumatoid factor, anti-SSA/SSB), and short disease duration (<4 years). Inclusion criteria for the MALT/primary SS group were primary SS and an associated MALT-type lymphoma (Ann Arbor stage IE) localized in the parotid gland. Patients were treated with 4 infusions of rituximab (375 mg/m2) given weekly after pretreatment with prednisone (25 mg) and clemastine. Patients were evaluated, using immunologic, salivary/lacrimal function, and subjective parameters, at baseline and at 5 and 12 weeks after the first infusion. RESULTS: Significant improvement of subjective symptoms and an increase in salivary gland function was observed in patients with residual salivary gland function. Immunologic analysis showed a rapid decrease of peripheral B cells and stable levels of IgG. Human anti-chimeric antibodies (HACAs) developed in 4 of 15 patients (27%), all with early primary SS. Three of these patients developed a serum sickness-like disorder. Of the 7 patients with MALT/primary SS, complete remission was achieved in 3, and disease was stable in 3 and progressive in 1. CONCLUSION: Findings of this phase II study suggest that rituximab is effective in the treatment of primary SS. The high incidence of HACAs and associated side effects observed in this study needs further evaluation.     

Rituximab plus ASHAP for the treatment of patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma: a single-centre study of 20 patients

The anti-CD20 antibody rituximab improves the results of first-line therapy in aggressive non-Hodgkin’s lymphoma (NHL) of B cell lineage. The purpose of this retrospective study was to evaluate its efficacy and toxicity in combination with the doxorubicine, methylprednisolone, high-dose cytarabine, cisplatin (ASHAP) protocol, an established treatment regimen for relapsed or refractory aggressive NHL. After a median of four cycles, 9 of 20 patients treated achieved a complete remission and 6 a partial remission, resulting in a total response rate of 75%. Remissions were not only seen in patients with relapsed lymphomas but also in patients with primary refractory or transformed indolent lymphomas. The outcome in cases with an international prognostic index score ≥2 was poor. Five of 15 responders received consolidating high-dose therapy with autologous stem cell transplantation. All of them are in ongoing remission. The main toxicity was myelosuppression, with neutropenias or thrombocytopenias of World Health Organization (WHO) grades III or IV developing in more than 90% of the cycles. There was one therapy-related death due to neutropenic sepsis. Non-hematologic toxicity was generally mild. At the time of analysis, six patients have died. After a median observation time of 17.5 months, the 2-year overall survival rate is 62%. ASHAP plus rituximab is an active and well-tolerated salvage protocol for patients with relapsed or refractory aggressive NHL, which compares favourably with other immuno-chemotherapy regimens, especially in patients with primary refractory or transformed indolent lymphomas.     

Simultaneous phenotypically distinct but clonally identical mucosa-associated lymphoid tissue and follicular lymphoma in a patient with Sj?gren's syndrome.

A 44-year-old woman with a 12-year history of Sj?gren's syndrome (SS) developed a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the parotid gland. Two years later, she presented with generalized lymphadenopathy and hepatosplenomegaly and a follicular lymphoma was diagnosed. To investigate the relationship of the two histologically distinct lymphomas, we re-examined their histology and immunophenotype and studied the lymphomatous tissue from the parotid, cervical lymph node, and spleen using molecular genetic methods. Histologic and immunophenotypic studies confirmed the previous diagnoses and also identified a previously unnoticed focus of follicular lymphoma in the second parotid gland biopsy. Polymerase chain reaction (PCR) amplification of the rearranged Ig heavy-chain gene showed the same sized dominant product in the MALT lymphoma and the follicular lymphoma. Similarly, PCR analysis of the t(14:18) translocation yielded an identical sized band from both MALT and follicular lymphoma. Cloning and sequencing of the Ig PCR products showed an identical CDR3 sequence from each lesion, indicating a common clonal lineage. The follicular lymphoma of the parotid gland lymph node and the follicular lymphoma of the spleen showed an identical mutation signature to that of the salivary gland MALT lymphoma. We propose that follicular lymphoma in the parotid gland lymph node may have resulted from colonization of lymphoid follicles by MALT lymphoma cells, following which the tumor cells were induced to express a follicular lymphoma phenotype, due to Bcl-2 overexpression caused by t(14;18), leading to a change in clinical behavior resulting in rapid widespread dissemination of disease. These observations suggest that the distinct phenotypes of low-grade B-cell lymphomas may be the consequence of interplay between genetic and local microenvironmental factors.     

Final results of a phase II study of CHOEP plus lenalidomide as initial therapy for patients with stage II–IV peripheral T-cell lymphoma

There remains no one standard induction for nodal-based peripheral T-cell lymphoma (PTCL). We conducted a phase II study of lenalidomide plus CHOEP as a novel induction strategy. Patients received CHOEP at standard doses in combination with 10 mg of lenalidomide on days 1–10 of a 21-day cycle for six cycles of therapy followed by observation, high-dose therapy with autologous stem cell rescue, or maintenance lenalidomide per provider preference. Among 39 patients evaluable for efficacy, the objective response rate after six cycles was 69%, with complete response in 49%, partial response in 21%, stable disease in 0% and progressive disease in 13%. Thirty-two patients (82%) completed full induction, and seven patients (18%) discontinued for toxicity, primarily hematologic. Any grade hematologic toxicity occurred in over 50% of patients, with grade 3 or 4 febrile neutropenia occurring in 35% of patients despite mandated growth factors. With a median followup of surviving patients of 21.3 months, the estimated 2-year progression-free and overall survival were 55% (95% CI 37%–70%) and 78% (95% CI 59%–89%), respectively. In sum, six cycles of lenalidomide plus CHOEP resulted in a modest response rate primarily due to hematologic toxicity, which prevented all patients from completing planned induction.     

Multicenter phase II study of plitidepsin in patients with relapsed/refractory non-Hodgkin’s lymphoma

This phase II clinical trial evaluated the efficacy, safety and pharmacokinetics of plitidepsin 3.2 mg/m² administered as a 1-hour intravenous infusion weekly on days 1, 8 and 15 every 4 weeks in 67 adult patients with relapsed/refractory aggressive non-Hodgkin’s lymphoma. Patients were divided into two cohorts: those with non-cutaneous peripheral T-cell lymphoma (n=34) and those with other lymphomas (n=33). Efficacy was evaluated using the International Working Group criteria (1999). Of the 29 evaluable patients with non-cutaneous peripheral T-cell lymphoma, six had a response (overall response rate 20.7%; 95% confidence interval, 8.0%–39.7%), including two complete responses and four partial responses. No responses occurred in the 30 evaluable patients with other lymphomas (including 27 B-cell lymphomas). The most common plitidepsin-related adverse events were nausea, fatigue and myalgia (grade 3 in <10% of cases). Severe laboratory abnormalities (lymphopenia, anemia, thrombocytopenia, and increased levels of transaminase and creatine phosphokinase) were transient and easily managed by plitidepsin dose adjustments. The pharmacokinetic profile did not differ from that previously reported in patients with solid tumors. In conclusion, plitidepsin monotherapy has clinical activity in relapsed/refractory T-cell lymphomas. Combinations of plitidepsin with other chemotherapeutic drugs deserve further evaluation in patients with non-cutaneous peripheral T-cell lymphoma. (clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00884286","term_id":"NCT00884286"}}NCT00884286)     

Extranodal marginal zone B-cell lymphoma of the lung in Sjögren's syndrome patients: reappraisal of clinical, radiological, and pathology findings

BACKGROUND: Primary Sj?gren's syndrome (pSs) is an autoimmune rheumatic disease that may express in a small number of patients a spectrum of lymphoproliferative diseases. The aim of this study was to describe clinical, imaging and pathology features of the extranodal marginal zone B-cell lymphoma (MZCL) of the lung of mucosa-associated lymphoid tissue (MALT) type in patients with pSs. METHODS: All patients (N=10) with biopsy proven MZCL of the lung of MALT type diagnosed in a tertiary teaching hospital during the last 7 years were studied. RESULTS: Seven patients had pSs. Almost all patients presented an indolent clinical course, contrasting strongly with the spectacular radiological findings in both chest roentgenograms and computed tomography. Pathology infiltration patterns observed were either nodular, peribronchial-perivascular, alveolar, or interstitial. Immunohistochemical study in all cases showed B cell phenotypes. Immunoglobulin light chain restriction was demonstrated in all patients. Monoclonal IgM(kappa) was evident in 5/7, IgM(lambda) in 1/7 and IgG (kappa) in 1/7 of patients. CONCLUSIONS: Lung MZCL associated with pSs are characterized by an important dissociation between clinical expression and radiological pattern. Clinical presentation and imaging features are not specific. Therefore, histologic documentation is mandatory to ensure diagnosis. Various chemotherapeutic agents in combination with rituximab lead to partial or complete remission in the majority of patients.     

Is there a benefit to adding rituximab to CHOP in the overall survival of patients with B-cell non-Hodgkin's lymphoma in a developing country?

Rituximab (R) has changed the prognosis of patients with non-Hodgkin's lymphoma (NHL) in developed countries, but its role has not been analyzed in underprivileged circumstances. One hundred and two patients with NHL treated in a developing country were analyzed: 28 patients with follicular lymphoma (FL) and 74 with diffuse large B-cell lymphoma (DLCL). Patients were treated upfront with either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or R-CHOP; the decision to employ R depending solely on the ability of patients to defray it. In DLCL, 42 were given CHOP and 32 R-CHOP, whereas in FL, 19 were given CHOP and 9 R-CHOP. The impact of the addition of R was found to be clearer in FL than in DLCL. In patients with DLCL, the overall survival (OS) was 87% at 80 months for those treated with R-CHOP and 84% at 145 months for those treated with CHOP (not significant). In patients with FL, the OS was 89% at 88 months for those treated with R-CHOP and 71% at 92 months for those treated with CHOP (P = 0··05). In a multivariate analysis, other variables which were identified to be associated with the OS were IPI and number of cycles in DLCL. It is concluded that R produced a mild positive impact in the OS of patients with FL, but not in those with DLCL. Since the addition of R results in a 36-fold increase in treatment costs, these observations may be important to decide therapeutic approaches in NHL patients living in underprivileged circumstances.     

Assessment of biological prognostic factors provides clinically relevant information in patients with diffuse large B-cell lymphoma—a Nordic Lymphoma Group study

The purpose of this study was to investigate the prognostic effects of four biological markers, BCL2, TP53, Ki-67, and P-glycoprotein, and their possible clinical relevance in addition to the international prognostic index (IPI) in diffuse large B-cell lymphoma (DLBCL). A total of 405 patients with aggressive lymphoma, stage II-IV, between 18 and 67 years, were randomized in a trial comparing CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin). Of these, 267 cases were classified as DLBCL, with adequate paraffin blocks available in 207 cases, enabling immunohistochemical assessment of the expression of BCL2, TP53, P-glycoprotein, and Ki-67. In a multivariate analysis, stratified for IPI, high BCL2 expression (>10%) low (<60%) expression of Ki-67, and high TP53 protein expression (>75%) were shown to provide additional prognostic information with regard to overall or failure-free survival. We found no association between expression of P-glycoprotein and outcome. Assessment of BCL2 positivity might be introduced as part of the routine investigation in patients with DLBCL, but further studies are necessary to confirm the clinical relevance of Ki-67 and TP53 expression.     

Waldeyer’s ring marginal zone B cell lymphoma: are the clinical and prognostic features nodal or extranodal? A study by the Consortium for Improving Survival of Lymphoma (CISL)

There has been controversy surrounding Waldeyer??s ring (WR), especially focused on the question of whether it should be regarded as a nodal or an extranodal site. We conducted retrospective analyses of marginal zone B cell lymphomas involving WR (WR-MZLs) to observe their clinical features and prognosis, with specific regard to the nodal-or-extranodal question. A total of 52 patients with histological diagnosis of WR-MZL were retrospectively analyzed. The most common involvement site was the tonsil (40.4?%). Ann Arbor stage III/VI disease was present in 48.1?% (25 of 52). The response rate of the 27 stage I/II patients was 88.9?%, with 21 complete remissions and three partial remissions. The median time to progression (TTP) was 3.7?years (95?% CI 2.5?C4.9?years). The estimated 5-year TTP and overall survival rates were 39.4 and 90.5?%, respectively. In a comparison with the historical data regarding extra-WR MALT lymphoma and nodal MZL (N-MZL), MALT lymphoma showed better TTP results than did WR-MZL and N-MZL (P?<?0.001).     

Positron emission tomography in the staging of patients with Hodgkin’s lymphoma. A prospective multicentric study by the Intergruppo Italiano Linfomi

In this prospective multicentric study, we investigated the contribution of positron emission tomography (PET) scanning to the staging of Hodgkin’s lymphoma (HL) by computed tomography (CT) and attempted to determine whether it has any impact on therapeutic approach. One hundred eighty six consecutive patients with HL from six Italian centers were enrolled in this study. They were staged with conventional methods; 2-[fluorine-18]fluoro-2-deoxy-d-glucose PET scanning were prospectively compared to CT. CT and FDG-PET stages were concordant in 156 patients (84%) and discordant in 30 patients (16%). PET stage in comparison to CT stage was higher in 27 patients (14%) and lower in 3 patients (1%). The programmed treatment strategy was modified in 11 out of 30 patients (37%) after the definition of final stage. If we considered the 123 CT staged patients with localized stage, ten patients (8%) with a change of stage from localized to advanced after PET evaluation were treated with different strategy. FDG-PET was shown to be a relevant, non-invasive method that supplements conventional procedures and should therefore be used routinely to stage HL, particularly in early stage patients, where a change in stage may modify disease management.     

A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin’s lymphoma

In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m²; cohort II: 20 mg/m²) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m² chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL.The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the US Army or the Department of Defense.John Byrd, Michael Grever, Ian Flinn, and Jamie Waselenko have submitted a patent for this regimen.     

A multicenter phase II study of the efficacy and safety of docetaxel plus cisplatin in Asian chemonaïve patients with metastatic or locally advanced non-small cell lung cancer

AIMS: To evaluate the efficacy and safety of docetaxel-cisplatin in patients with metastatic or locally advanced non-small cell lung cancer (NSCLC). METHODS: Chemotherapy-na?ve patients with histologically confirmed TNM stage III or IV NSCLC were recruited from 12 Asian trial centers. Patients received docetaxel (75 mg/m2) and cisplatin (75 mg/m2) every 3 weeks for 6 cycles. RESULTS: 130 of 146 patients were evaluable for efficacy (60% stage IV). Three complete and 58 partial responses were observed (overall response rate: 46.9%; 95% CI: 38.3-55.5%). Median time to progression was 6.9 months and median survival was 14.0 months; 1-year survival was 59.5%. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 69.2%, 6.2% and 18.5% of patients, respectively. Grade 3/4 vomiting was observed in 13.7% and grade 3/4 neurosensory effects were observed in 2.7% of patients. There was one case of treatment-related death due to sepsis. CONCLUSION: Docetaxel-cisplatin is an effective and well-tolerated treatment in Asian patients with NSCLC.     

Induction therapy with the MATRix regimen in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system – an international study of feasibility and efficacy in routine clinical practice

The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). However, nothing is known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28–78) and 2 (range 0–4). The overall response rate after MATRix was 79%. Nine (6%) treatment-related deaths were recorded. After a median follow-up of 27.4 months (95% confidence interval [CI] 24.4–31.9%), the two-year progression-free and overall survival were 56% (95% CI 48.4–64.9%) and 64.1% (95% CI 56.7–72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non-trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.     

First-line chemotherapy with planned sequential administration of cisplatin/gemcitabine followed by docetaxel in elderly ‘unfrail’ patients with advanced non-small-cell lung cancer: a multicenter phase II study

Purpose

The role of cisplatin in the first-line treatment for elderly advanced non-small-cell lung cancer is not completely defined. We previously reported in this subset of patients an interesting efficacy and tolerability of a sequential schedule of gemcitabine followed by docetaxel.

Methods

Patients aged?≥70?years and with Eastern Cooperative Oncology Group performance status 0 or 1 received cisplatin 60?mg/m² on Day 1 and gemcitabine 1,000?mg/m² on Day 1 and 8 every 3?weeks for 3 courses followed by 3 courses of docetaxel 37.5?mg/m² on Day 1 and 8 every 3?weeks, provided there was no evidence of disease progression. Patients were excluded if considered ‘frail’ according to the Multidimensional Geriatric Assessment. The main objective of the study was the 4-month progression-free survival rate. Simon’s two-stage minimax design was applied to calculate the sample size.

Results

After 30 patients were enroled into the study, the 4-month progression-free survival rate was 53.3?% and the study was closed at the first stage for futility; the overall response rate was 16.7?%; the median time to progression and median duration of survival were 5.1 and 8.6?months, respectively; the 1-year survival rate was 30?%.

Conclusion

The incorporation of cisplatin in a sequential schedule of gemcitabine followed by docetaxel is feasible but did not yield a substantial advantage to deserve further investigations.