High‐dose therapy and autologous stem cell transplantation in marginal zone lymphomas: a retrospective study by the EBMT Lymphoma Working Party and FIL‐GITMO

The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non‐transformed nodal, extra‐nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1–8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy‐based high‐dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub‐group and more transplants performed in recent years in the other sub‐groups. After a median follow‐up of 5 years, 5‐year cumulative incidence of relapse/progression and non‐relapse mortality were 38% and 9%, respectively. Five‐year event‐free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five‐year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.     

A multicentre,phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B‐cell lymphoma

This international, multicentre phase II study was conducted to assess ofatumumab, a human anti‐CD20 monoclonal antibody, in patients with relapsed/progressive diffuse large B‐cell lymphoma (DLBCL) who were ineligible for autologous stem cell transplantation (TI) or who had relapse/progression after transplantation (PT). Eighty‐one patients received ofatumumab 300 mg intravenously (IV) on Day 1, followed by seven weekly IV infusions of 1000 mg. Patients in the TI and PT groups had received a median of 3 (range, 1–7) and 5 (range, 2–7) prior therapies, respectively. One‐third of patients did not respond to the last prior therapy, and 53% had failed two or more rituximab‐containing therapies. Overall response rate was 13% for the TI group (seven partial responses) and 8% for the PT group (two complete responses). Median progression‐free survival was 2·6 months, and median duration of response was 9·5 months. The most common Grade 3–4 adverse events were neutropenia (11%), leucopenia (6%), lymphopenia (6%) and thrombocytopenia (6%). Sixteen deaths have been reported, with disease progression as the most common cause of death. In conclusion, ofatumumab monotherapy was well tolerated and provided clinical benefit to some DLBCL patients in this study. This trial was registered at www.clinicaltrials.gov (NCT00622388).     

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.     

Endoscopic removal of primary B‐cell mucosa‐associated lymphoid tissue lymphoma of the cecum

A 61‐year‐old woman with a history of positive fecal occult blood test was referred for further evaluation. She was symptom‐free and had no family history of colorectal cancer. Colonoscopy revealed a semipedunculated polyp with a surface of normal appearance. Although a biopsy specimen revealed inflammatory cells including numerous small lymphocytes in the mucosa, a definitive diagnosis was not made. Four weeks later, endoscopic removal using the submucosal injection method was performed for diagnosis as well as treatment. The tumor measured 14 × 13 × 6 mm. The pathological diagnosis was low‐grade B‐cell mucosa‐associated lymphoid tissue (MALT) lymphoma, and the depth of invasion was estimated as the submucosal layer. The case described here suggests that MALT lymphoma should be added to the differential diagnosis of colorectal submucosal tumors, and some cases of them might be resected endoscopically using the submucosal injection method.     

Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma: post‐hoc analyses from a phase III trial

This post hoc analysis of a phase 3 trial explored the effect of pixantrone in patients (50 pixantrone, 47 comparator) with relapsed or refractory aggressive B‐cell non‐Hodgkin lymphoma (NHL) confirmed by centralized histological review. Patients received 28‐d cycles of 85 mg/m² pixantrone dimaleate (equivalent to 50 mg/m² in the approved formulation) on days 1, 8 and 15, or comparator. The population was subdivided according to previous rituximab use and whether they received the study treatment as 3rd or 4th line. Median number of cycles was 4 (range, 2–6) with pixantrone and 3 (2–6) with comparator. In 3rd or 4th line, pixantrone was associated with higher complete response (CR) (23·1% vs. 5·1% comparator, P = 0·047) and overall response rate (ORR, 43·6% vs. 12·8%, P = 0·005). In 3rd or 4th line with previous rituximab (20 pixantrone, 18 comparator), pixantrone produced better ORR (45·0% vs. 11·1%, P = 0·033), CR (30·0% vs. 5·6%, P = 0·093) and progression‐free survival (median 5·4 vs. 2·8 months, hazard ratio 0·52, 95% confidence interval 0·26–1·04) than the comparator. Similar results were found in patients without previous rituximab. There were no unexpected safety issues. Pixantrone monotherapy is more effective than comparator in relapsed or refractory aggressive B‐cell NHL in the 3rd or 4th line setting, independently of previous rituximab.     

Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre,single‐arm,phase 2 study

The multicentre, open‐label, two‐stage, single‐arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)‐1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. Fifty‐eight patients were enrolled from August 2008–January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5–17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5–6·1) and 16·9 months (95% CI 14·4–29·9), respectively. Grade 3/4 non‐haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted.     

Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B‐cell lymphoma: mature results of a phase II multicentre study

Salvage therapy followed by high‐dose therapy (HDT) remains a mainstay for patients with relapsed lymphoma, however no optimal regimen has been defined. Here we report on the results of R‐DexaBEAM (rituximab, dexamethasone, carmustine, etoposide, cytarabine, melphalan) followed by HDT. Patients aged 18–65 years, Eastern Cooperative Oncology Group performance score 0–2, with relapsed/refractory B‐cell non‐Hodgkin lymphoma (NHL) were eligible. R‐Dexa‐BEAM was given for two cycles followed by stem cell mobilization and HDT. Primary endpoint of the trial was progression‐free‐survival (PFS). One hundred and three patients were included: aggressive NHL (aNHL): diffuse large B‐cell lymphoma 55, mantle cell lymphoma 7, follicular lymphoma (FL) grade 3: 5, indolent Lymphoma (iNHL): FL grade 1–2: 29, marginal zone lymphoma 6, Immunocytoma 1. The overall response rate after salvage therapy was 62% for aNHL and 78% for iNHL patients. 66% of patients with aNHL and 86% with iNHL underwent HDT. Treatment‐related mortality for HDT was 1·3%. For aNHL patients, the median PFS was 0·83 years with 44% alive at the median follow‐up of 7·3 years. Corresponding figures for iNHL were: median PFS 3·7 years and 72% alive after 8 years. The combination of rituximab with DexaBEAM followed by HDT resulted in high response rates and sustained remissions in responders. R‐DexaBEAM followed by HDT can be considered a valid salvage option for NHL.     

A randomized phase II study of standard‐dose versus high‐dose rituximab with BEAM in autologous stem cell transplantation for relapsed aggressive B‐cell non‐hodgkin lymphomas: long term results

High‐dose rituximab (HD‐R) combined with carmustine, cytarabine, etoposide and melphalan (BEAM) and autologous stem cell transplant (ASCT) was effective and tolerable in a single‐arm prospective study of relapsed aggressive B‐cell non‐Hodgkin lymphoma (R‐NHL). We performed a randomized phase 2 study comparing HD‐R versus standard‐dose rituximab (SD‐R) in R‐NHL. Ninety‐three patients were randomized to HD‐R (1000 mg/m²) (n = 42) or SD‐R (375 mg/m²) (n = 51) administered on post‐transplant days +1 and +8, using a Bayesian adaptive algorithm. The 2 treatment arms were balanced in regards to patient demographic and clinical characteristics. At a median follow‐up of 7·92 years, the 5‐year disease‐free survival (DFS) and overall survival (OS) were 40% and 48%, respectively. We found no statistically significant differences between HD‐R and SD‐R in 5‐year DFS (36% vs. 43%; P = 0·205) and OS (43% vs. 52%; P = 0·392). In multivariate analyses, only disease status before ASCT [residual disease versus complete remission (CR)] (hazard ratio [HR] 1·79, 95% confidence interval [CI]: 1·08–2·95) and number of prior treatments received (>2 vs. ≤2 lines of treatment) (HR 1·89, 95% CI: 1·13–3·18) were associated with worse DFS and OS. Patients who had SCT while in CR or who received ≤2 lines of treatment prior to SCT had better 5‐year OS (57% vs. 35%; P = 0·02 and 54% vs. 30%, P = 0·001, respectively) in both arms. No differences in engraftments or adverse events were noted in the 2 arms. When combined with BEAM and ASCT in relapsed aggressive B‐cell NHL, HD‐R provided no DFS or OS advantage over SD‐R. In patients who have been exposed to rituximab in the frontline or salvage setting, the addition of rituximab in the peri‐transplant setting remains controversial.     

A phase I/II trial of bortezomib combined concurrently with gemcitabine for relapsed or refractory DLBCL and peripheral T‐cell lymphomas

There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) and peripheral T‐cell lymphoma (PTCL). We conducted a phase I/II trial with bortezomib (dose‐escalated to 1·6 mg/m²) given concurrently with gemcitabine (800 mg/m²) days 1 + 8 q21 d. Of 32 patients, 16 each had relapsed/refractory PTCL and DLBCL. Median prior therapies were 3 and 35% had failed transplant. Among the first 18 patients, 67% experienced grade 3/4 neutropenia and/or grade 3/4 thrombocytopenia resulting in repeated treatment delays (relative dose intensity: 46%). Thus, the study was amended to give bortezomib and gemcitabine days 1 + 15 q28 d, which resulted in markedly improved tolerability. Among all patients, the overall response rate (ORR) was 24% with 19% complete remission (CR; intent‐to‐treat (ITT) ORR 16%, CR 13%), which met criteria for futility. The ORR for DLBCL was 10% (CR 10%) vs. 36% for PTCL (CR 27%). Among 6 PTCL patients treated on the modified schedule, ORR by ITT was 50% (CR 30%). Altogether, concurrent bortezomib/gemcitabine given days 1 + 8 q21 d was not tolerable, while modification to a bi‐monthly schedule allowed consistent treatment delivery. Whereas efficacy of this combination was low in heavily pre‐treated DLBCL, there was a signal of activity in relapsed/refractory PTCL utilizing the modified schedule.     

Guidelines for the management of diffuse large B‐cell lymphoma

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8–10 months. We conducted a phase II trial of standard CHOP‐21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2–6: 1000 mg day 1) (CHOP‐O) followed by 12 months ofatumumab maintenance (1000 mg given 8‐weekly for up to six cycles). Forty‐three patients were recruited of whom 37 were evaluable. Seventy‐three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide‐based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression‐free survival was 6·2 months (95% confidence interval [CI] 4·9–14·0 months) and median OS was 11·4 months (95% CI 6·4–25·6 months). Treatment‐naïve and TP53‐intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non‐neutropenic infections were observed. There were no treatment‐related deaths. Seven patients received platinum‐containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP‐O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.     

Prospective subgroup analyses of the randomized MCL‐002 (SPRINT) study: lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma

In the mantle cell lymphoma (MCL)‐002 study, lenalidomide demonstrated significantly improved median progression‐free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long‐term follow‐up data and results of preplanned subgroup exploratory analyses from MCL‐002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL‐002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1–21; 28‐day cycles) or single‐agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent‐to‐treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single‐agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history.     

Long‐term treatment of localized gastric marginal zone B‐cell mucosa associated lymphoid tissue lymphoma including incidence of metachronous gastric cancer

Background and Aim: According to a few recent reports on the long‐term clinical outcome of gastric marginal zone B‐cell mucosa associated lymphoid tissue lymphoma (MALT lymphoma); localized gastric MALT lymphoma generally has a favorable prognosis. However, the risk of metachronous gastric cancer has not been evaluated. In this study, we analyzed long‐term outcomes of localized gastric MALT lymphoma including the incidence of metachronous gastric cancer. Methods: Between April 1996 and May 2008, 60 patients (31 men and 29 women; mean age 58.1 years) with localized gastric MALT lymphoma (stage I and II¹ according to Lugano classification) were analyzed retrospectively. Results: Forty‐eight patients (82.6%) achieved complete remission by eradication therapy. Radiation therapy was conducted on eight patients as second‐line treatment, and all of them achieved remission. The median follow‐up period was 76 months (range, 12–157 months). One patient had local relapse after remission for 5 years and three patients developed early gastric cancer without recurrence of lymphoma (5%). All of the three gastric cancers appeared in the same areas where MALT lymphoma had been eradicated. Conclusion: Eradication therapy and radiation therapy for localized gastric MALT lymphoma have a favorable long‐term outcome, though regular follow‐up endoscopy should be performed for detecting metachronous early gastric cancer.     

Front‐line management of indolent non‐Hodgkin lymphoma in Australia. Part 2: mantle cell lymphoma and marginal zone lymphoma

Mantle cell lymphoma (MCL) and the marginal zone lymphoma (MZL) subtypes (nodal MZL, extra‐nodal MZL of mucosa‐associated lymphoid tissue (MALT lymphoma) and splenic MZL) are uncommon lymphoma subtypes, accounting for less than 5–10% of all non‐Hodgkin lymphoma. The evidence base for therapy is therefore limited and enrolment into clinical trials is preferred. Outcomes for patients with MCL have been steadily improving mainly due to the adoption of more intense strategies in younger patients, the use of rituximab maintenance and the recent introduction of bendamustine in older patients. MZL is a more heterogeneous group of cancer with both nodal, extra‐nodal and splenic subtypes. Extranodal MZL may be associated with autoimmune or infectious aetiologies, and can respond to eradication of the causative pathogen. Proton pump inhibitor plus dual antibiotics in Helicobacter pylori positive gastric MALT lymphoma is curative in many patients. Watchful waiting is appropriate in most patients with asymptomatic advanced stage disease, which tends to behave in a particularly indolent manner. Other options for symptomatic disease include splenectomy, chemoimmunotherapy with rituximab and, more recently, targeted therapies.     

Clinicopathologic analysis of ocular adnexal lymphomas: extranodal marginal zone b-cell lymphoma constitutes the vast majority of ocular lymphomas among Koreans and affects younger patients

The majority of ocular adnexal lymphomas (OAL) are primary marginal zone B-cell lymphomas (MALT lymphomas). The present study correlated the clinicopathological variables with the histologic subtypes by World Health Organization (WHO) classification with emphasis on MALT lymphomas in OALs of Koreans. There were 68 cases (31 males and 37 females), with a mean age of 45.9 years (range 7-89 years). Histologically, 61 MALT-type, 2 diffuse large B-cell (DLBCL), 2 mantle cell type (MCL), 1 anaplastic large-cell (ALCL), and 2 NK/T-cell lymphomas (NK/T-L) were counted among them. Fifty-seven were primary cases (P-OAL), and 11 were secondary cases (S-OAL). Nearly all P-OALs were MALT lymphomas (n = 56, 98%), with an exception of 1 MCL. Eleven S-OALs included 5 MALT type, 2 DLBCL, 1 ALCL, 1 MCL, and 2 NK/T-L. All MALT lymphoma patients were alive (n = 59) except for 2 after a mean duration of follow-up of 27.6 months (range: 0-108 months): one died of an unrelated cause and one died of recurrence. One non-MALT type P-OAL was alive with no evidence of disease (42 months). Of the 11 S-OAL, 4 had marrow involvement and 5 had progression or relapse outside the orbit. Compared with the other subtypes, MALT lymphoma was more likely to present with local disease (P = 0.001), achieve complete remission (CR) (0.022), and be alive at last follow-up (0.197), and less likely to experience recurrence (P = 0.06). In conclusion, OALs in Koreans are characterized by a preponderance of primary lymphomas over systemic lymphomas, striking predominance of MALT type lymphomas, and young age of occurrence. Histologic subtype by WHO classification has a significant correlation with the final outcome, with the most favorable outcome associated with OALs of the MALT type.     

Overall survival of children and adolescents with mature B cell non‐Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group

We determined the risk factors associated with poor survival in children and adolescents with de novo mature B cell non‐Hodgkin lymphoma (B‐NHL) who had refractory or relapsed disease during or after the French‐American‐British mature lymphoma B (FAB/LMB) 96 multi‐agent chemotherapy. Among the 1 111 registered on study, 104 patients (9·4%) had refractory disease or disease relapse after first complete remission. Among these 104 patients, 28 (27%) patients had refractory disease and 76 (73%) had relapsed disease. The estimated 1‐ and 2‐year overall survival (OS) (95% confidence interval) was 31·5% (23·3–41·0%) and 22·3% (15·3–31·4%), respectively. Prognostic analysis of OS using a Cox multivariate model showed that factors independently associated with OS included lactate dehydrogenase ≥2 upper normal limit [hazard ratio (HR) = 2·86 (1·57–5·2), P = 0·0006]; time to failure (>6 months) [HR = 0·59 (0·36–0·97), P = 0·038]; and failure in bone marrow [HR = 2·78 (1·65–4·68), P = 0·0001]. New therapeutic strategies are required to significantly reduce refractory disease and disease relapse in patients with newly diagnosed mature B‐NHL and, more importantly, there is a critical need to develop novel retrieval approaches in patients with chemotherapy‐resistant disease.